Using Respiratory Motion to Guide Planning Target Volume Margins for External Beam Partial Breast Irradiation

Abstract

Although toxicity associated with external-beam accelerated partial breast irradiation (APBI) has been reported to be acceptable in some studies, others have shown higher rates of fibrosis and suboptimal cosmesis using the fractionation schedule of 385 cGy twice daily to 3850 cGy. Given that this fractionation schedule may be close to the limits of normal tissue toxicity, any reduction in irradiated normal tissue volume that can be achieved without compromising target coverage may have meaningful clinical significance. Recent studies have explored the use of image guidance to reduce the planning target volume (PTV) margin required to accommodate setup errors. There have also been many recent studies of respiratory motion in patients treated with APBI in the supine position (1Baglan K.L. Sharpe M.B. Jaffray D. et al.Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).Int J Radiat Oncol Biol Phys. 2003; 55: 302-311Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar, 3Becker S.J. Patel R.R. Mackie T.R. 4DCT intrafraction motion margin assessment in breast cancer treatments [abstract].Radiother Oncol. 2005; 76: S74Abstract Full Text PDF Google Scholar, 4Ahn S. Analysis of breast motion with 4 dimensional computerized tomography simulator [abstract].Int J Radiat Oncol Biol Phys. 2006; 66: S230-S231Abstract Full Text Full Text PDF Google Scholar, 5Bert C. Metheany K.G. Doppke K.P. et al.Clinical experience with a 3D surface patient setup system for alignment of partial-breast irradiation patients.Int J Radiat Oncol Biol Phys. 2006; 64: 1265-1274Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 6Chopra S. Dinshaw K.A. Kamble R. Sarin R. Breast movement during normal and deep breathing, respiratory training and set up errors: implications for external beam partial breast irradiation.Br J Radiol. 2006; 79: 766-773Crossref PubMed Scopus (41) Google Scholar, 7Morrow N.V. Stepaniak C. White J. Wilson J.F. Li X.A. Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 69: 910-917Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar, 9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar, 10Park C.K. Zhang G. Forster K.M. Harris E.E.R. Evaluation of fiducial marker migration and respiratory-induced motion for image guided radiotherapy in accelerated partial breast irradiation [abstract].Int J Radiat Oncol Biol Phys. 2009; 75: S626-S627Abstract Full Text Full Text PDF PubMed Google Scholar, 11Penninkhof J. Quint S. de Boer H. et al.Surgical clips for position verification and correction of non-rigid breat tissue in simultaneously integrated boost (SIB) treatment.Radiother Oncol. 2009; 90: 110-115Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 12Price G.J. Sharrock P.J. Marchant T.E. et al.An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.Phys Med Biol. 2009; 54: 6515-6533Crossref PubMed Scopus (20) Google Scholar, 13Lee R. Suh H. Surgical clips for observation of respiratory motion of the breast via 2D fluoroscopy and 3D CT scans.J Korean Phys Soc. 2010; 56: 1852-1860Crossref Scopus (1) Google Scholar, 14Liao Z.W. Guan X.X. Li F.Y. et al.Accelerated partial breast irradiation: use of four-dimensional CT for target localization and assessment of intrafractional motion.Oncol Res. 2010; 18: 503-507Crossref PubMed Scopus (12) Google Scholar, 15Qi X.S. White J. Rabinovitch R. et al.Respiratory organ motion and dosimetric impact on breast and nodal irradiation.Int J Radiat Oncol Biol Phys. 2010; 78: 609-617Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 16Yue N.J. Goyal S. Zhou J. Khan A.J. Haffty B.G. Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.Int J Radiat Oncol Biol Phys. 2011; 79: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 18Bedi C. Kron T. Willis D. Hubbard P. Milner A. Chua B. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging.Clinical Oncology. 2011; 23: 601-607Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar), and it may be time to reevaluate the PTV margin required to accommodate respiratory motion as well.The 19 studies summarized in the following table report a wide range of target motion that, at its extremes, spans a whole order of magnitude. Harris et al. (19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar) reported the use of four-dimensional computed tomography (4D-CT) to track gold fiducial markers placed at the periphery of the surgical bed in 15 patients and found that “the average intrafraction respiration induced fiducial motion was 0.8 mm.” By contrast, Yue et al. reported an average CTV motion of 8.5 mm in 4D-CTs of 4 APBI patients (8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar). Of the 19 studies, the “take-home” motion magnitude was <2 mm in five studies, 2 to 4 mm in 10 studies, and >5 mm in 4 studies.TablePartial breast respiratory motion studiesStudyYearNModalityStructureMotion magnitudeMax or SDBaglan et al. 1Baglan K.L. Sharpe M.B. Jaffray D. et al.Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).Int J Radiat Oncol Biol Phys. 2003; 55: 302-311Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar200316Breath-hold CTSurgical clips6 mm9 mm (max)Lee et al. 2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar20047FluoroscopySurgical clips4 mm7 mm (max 1D)Becker et al. 3Becker S.J. Patel R.R. Mackie T.R. 4DCT intrafraction motion margin assessment in breast cancer treatments [abstract].Radiother Oncol. 2005; 76: S74Abstract Full Text PDF Google Scholar2005154D-CTMultiple structures2 mm2.5 mm (max)Ahn 4Ahn S. Analysis of breast motion with 4 dimensional computerized tomography simulator [abstract].Int J Radiat Oncol Biol Phys. 2006; 66: S230-S231Abstract Full Text Full Text PDF Google Scholar2006214D-CT and fluoroscopySurgical clips1.4 mm0.6 mm (SD)Bert et al. 5Bert C. Metheany K.G. Doppke K.P. et al.Clinical experience with a 3D surface patient setup system for alignment of partial-breast irradiation patients.Int J Radiat Oncol Biol Phys. 2006; 64: 1265-1274Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar20067Surface ImagingSurface1.9 mm1.1 mm (SD)Chopra et al. 6Chopra S. Dinshaw K.A. Kamble R. Sarin R. Breast movement during normal and deep breathing, respiratory training and set up errors: implications for external beam partial breast irradiation.Br J Radiol. 2006; 79: 766-773Crossref PubMed Scopus (41) Google Scholar20065FluoroscopySurface BBs2.9 mm5 mm (max 1D)Morrow et al. 7Morrow N.V. Stepaniak C. White J. Wilson J.F. Li X.A. Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 69: 910-917Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar200734D-CTChest wall2.3 mm0.9 mm (SD)Yue et al. 8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar200744D-CTCTV8.5 mm11 mm (max)Afghan et al. 9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar20092CalypsoCalypso7 mm8 mm (max 1D)Park et al. 10Park C.K. Zhang G. Forster K.M. Harris E.E.R. Evaluation of fiducial marker migration and respiratory-induced motion for image guided radiotherapy in accelerated partial breast irradiation [abstract].Int J Radiat Oncol Biol Phys. 2009; 75: S626-S627Abstract Full Text Full Text PDF PubMed Google Scholar2009154D-CTGold markers1.5 mm1 mm (SD)Penninkhof et al. 11Penninkhof J. Quint S. de Boer H. et al.Surgical clips for position verification and correction of non-rigid breat tissue in simultaneously integrated boost (SIB) treatment.Radiother Oncol. 2009; 90: 110-115Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar200915FluoroscopySurgical clips2.4 mm0.6 mm (SD)Price et al. 12Price G.J. Sharrock P.J. Marchant T.E. et al.An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.Phys Med Biol. 2009; 54: 6515-6533Crossref PubMed Scopus (20) Google Scholar200912Surface imagingSurface3 mm8 mm (max)Lee et al. 13Lee R. Suh H. Surgical clips for observation of respiratory motion of the breast via 2D fluoroscopy and 3D CT scans.J Korean Phys Soc. 2010; 56: 1852-1860Crossref Scopus (1) Google Scholar201015Breath-hold CTSurgical clips7 mm4 mm (SD)Liao et al. 14Liao Z.W. Guan X.X. Li F.Y. et al.Accelerated partial breast irradiation: use of four-dimensional CT for target localization and assessment of intrafractional motion.Oncol Res. 2010; 18: 503-507Crossref PubMed Scopus (12) Google Scholar201094D-CTCavity2.6 mm0.8 mm (SD)Qi et al. 15Qi X.S. White J. Rabinovitch R. et al.Respiratory organ motion and dosimetric impact on breast and nodal irradiation.Int J Radiat Oncol Biol Phys. 2010; 78: 609-617Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar2010184D-CTCavity2.3 mm1.3 mm (SD)Yue et al. 16Yue N.J. Goyal S. Zhou J. Khan A.J. Haffty B.G. Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.Int J Radiat Oncol Biol Phys. 2011; 79: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar201010FluoroscopyGold markers1.0 mm0.4 mm (SD)Kirby et al. 17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar2011264D-CTSurgical clips and chest wall3.3 mm6 mm (max 1D)Bedi et al. 18Bedi C. Kron T. Willis D. Hubbard P. Milner A. Chua B. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging.Clinical Oncology. 2011; 23: 601-607Abstract Full Text Full Text PDF Scopus (15) Google Scholar2011104D-CTSurgical clips3.7 mm6.5 mm (max)Harris et al. 19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar2011154D-CTGold markers0.8 mm0.6 mm (SD)Abbreviations: CT = computed tomography; Max = maximum; SD = standard deviation; 1D = one-dimensional; 4D = four-dimensional. Open table in a new tab One early study on the larger end of the spectrum is that by Baglan et al. (1Baglan K.L. Sharpe M.B. Jaffray D. et al.Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).Int J Radiat Oncol Biol Phys. 2003; 55: 302-311Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). Evaluating surgical clip positions in CTs of 16 patients acquired at normal inspiration and expiration breath-holds, they reported a mean motion of 6 mm (range, 3–9 mm). From this, they suggested that “a conservative margin of 5 mm around the CTV would completely account for breast motion during quiet respiration in all patients.” (Note that if a target is localized to its midventilation position, a symmetric breathing margin encompasses twice its value in target motion. In this case, a 5-mm symmetric margin was chosen to accommodate a potential 1-cm excursion.) Adding another 5-mm margin to account for setup error, Baglan et al. obtained a 1-cm PTV margin that has since been widely adopted and is part of the NSABP B-39/RTOG 0413 protocol. However, as seen above, most subsequent studies have reported target motions under 4 mm. This suggests that for most patients, the breathing component of the PTV margin can be reduced to ∼2 mm. If a dosimetric margin (as opposed to a full-range margin) is applied, the margin could be even smaller, although this has not been specifically demonstrated for partial breast radiotherapy. A margin reduction from 5 mm to 0–2 mm is significant and similar to the reduction that can be achieved with image guidance to reduce setup errors.Further reduction might be achieved by using nonuniform margins. Although a few studies have observed significant lateral respiratory motion of the target (2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar, 8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar, 9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar), most have reported motion primarily in the anterior–posterior and superior–inferior directions (4Ahn S. Analysis of breast motion with 4 dimensional computerized tomography simulator [abstract].Int J Radiat Oncol Biol Phys. 2006; 66: S230-S231Abstract Full Text Full Text PDF Google Scholar, 11Penninkhof J. Quint S. de Boer H. et al.Surgical clips for position verification and correction of non-rigid breat tissue in simultaneously integrated boost (SIB) treatment.Radiother Oncol. 2009; 90: 110-115Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 13Lee R. Suh H. Surgical clips for observation of respiratory motion of the breast via 2D fluoroscopy and 3D CT scans.J Korean Phys Soc. 2010; 56: 1852-1860Crossref Scopus (1) Google Scholar, 14Liao Z.W. Guan X.X. Li F.Y. et al.Accelerated partial breast irradiation: use of four-dimensional CT for target localization and assessment of intrafractional motion.Oncol Res. 2010; 18: 503-507Crossref PubMed Scopus (12) Google Scholar, 16Yue N.J. Goyal S. Zhou J. Khan A.J. Haffty B.G. Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.Int J Radiat Oncol Biol Phys. 2011; 79: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). At our institution, we have acquired 4D-CTs in patients receiving APBI (n = 8) with gold fiducial markers sutured to the walls of the lumpectomy cavity. In these patients, the maximum marker motion varied by an order of magnitude (range, 0.7–7.5 mm), but the maximum lateral motion out of all markers in all patients was 1.5 mm. On the basis of such data, nonuniform margins might be considered to reduce the irradiated volume in the medial–lateral direction.Although evidence suggests that margins may be safely reduced in most patients, the evidence for reducing margins for all patients is less firm. Any effort to reduce margins should therefore be accompanied by individual assessments of respiratory motion for each patient. In particular, it is important to be able to identify those patients on the tail end of the distribution that exhibit large breathing motion. Given the disagreement in the literature, it is not clear what proportion of the patient population this may represent. As mentioned above, an average motion >5 mm was seen in four of the studies cited here, but a greater number of studies did not report even a single patient moving >5 mm. (The remainder reported motion >5 mm at the top of their range, although the averages were lower. Of our eight patients, three exceeded 5 mm, and our mean was 4 mm.) The AAPM TG-76 report recommends management of respiratory motion exceeding 5 mm. In practice, such patients should not be hard to identify in a clinic equipped with fluoroscopy or 4D-CT or other respiratory tracking capability.If patient-specific assessment of respiratory motion is used, it will be important to verify the consistency of a patient’s breathing between simulation and treatments. Harris et al., Park et al., and Afghan et al. have all reported on multiple sessions of respiratory motion measurement (9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar, 10Park C.K. Zhang G. Forster K.M. Harris E.E.R. Evaluation of fiducial marker migration and respiratory-induced motion for image guided radiotherapy in accelerated partial breast irradiation [abstract].Int J Radiat Oncol Biol Phys. 2009; 75: S626-S627Abstract Full Text Full Text PDF PubMed Google Scholar, 19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar). In the first two studies, 4D-CTs were acquired at pretreatment simulation and at the end of treatment. Harris et al. reported that in 15 patients, “the average variation of respiratory motion pre- to post treatment was 0.0 mm (SD = 1.0 mm; range,−2.5 to 2.2 mm.)” Park et al. reported nearly identical results in 22 patients: “average variation in respiratory motion for individual fiducials was −0.1 mm (SD = 0.9 mm; range, −2.5 to 2.2 mm.)” By contrast, Aghan et al. reported that 2 patients with implanted electromagnetic transponders had respiratory motion ranges of 4.7 and 6.5 mm over seven and five fractions, respectively.Until this issue is better understood, intrafraction monitoring of patients with individualized respiratory margins is advisable. Possible monitoring techniques include fluoroscopy, 4D cone-beam CT, electromagnetic transponders, and surface tracking. The latter two have the advantage of not adding radiation dose to the patient, permitting continuous monitoring throughout treatment. However, surface imaging does not track target motion directly, nor does fluoroscopy in the absence of fiducial markers. Although some studies have relied on surrogates for the target, the relationship between surrogate and target motion is not well established. Becker et al. analyzed multiple features such as the surface, the chest wall, and the anterior and posterior edges of the cavity, but their abstract does not give results beyond noting that all observed motions were <2.5 mm (3Becker S.J. Patel R.R. Mackie T.R. 4DCT intrafraction motion margin assessment in breast cancer treatments [abstract].Radiother Oncol. 2005; 76: S74Abstract Full Text PDF Google Scholar). Kirby et al. (17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) and Bedi et al. (18Bedi C. Kron T. Willis D. Hubbard P. Milner A. Chua B. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging.Clinical Oncology. 2011; 23: 601-607Abstract Full Text Full Text PDF Scopus (15) Google Scholar) reported comparable motion of clips and chest wall, a finding that might be relevant in fluoroscopic verification. We can report that in our 8 patients, the magnitude of maximum nipple displacement and maximum individual clip displacement agreed in all patients within 2 mm. On average, the nipple underestimated maximum marker motion by 0.4 mm (SD, 1.1 mm). Also, a midline BB may be taken as a surrogate for the sternum, which can be tracked under fluoroscopy. In our patients, the BB underestimated the maximum marker motion by an average of 0.4 mm (SD, 1.1 mm), with a maximum discrepancy of 2.3 mm.Many studies have evaluated patients with multiple fiducial markers and reported average or maximum motion. One study by Lee et al. (2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar) presented fluoroscopic motion data for every marker they imaged (23 surgical clips in 7 patients). Their data show a difference of as much as 5 mm in the excursion of different clips in the same patient. Different parts of the target can move differently. A possibly related finding is reported by Price et al., (12Price G.J. Sharrock P.J. Marchant T.E. et al.An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.Phys Med Biol. 2009; 54: 6515-6533Crossref PubMed Scopus (20) Google Scholar) who observed in 12 patients that the lateral and, in some cases, superior parts of the breast surface moved more than the medial part, a finding corroborated by Morrow et al. (7Morrow N.V. Stepaniak C. White J. Wilson J.F. Li X.A. Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 69: 910-917Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Of our patients, 2 had individual clips whose motion magnitudes differed as much as 2–3 mm from each other. Unlike Price et al., when we observed differences in individual clip motion, it was always the most superior markers that moved the least. One other patient showed considerably more nonrigid target motion. Between inhalation and exhalation, the anterior–superior markers moved approximately 1 mm, whereas the other markers moved as much as 6 mm (Fig. 1). For such a patient, creating an internal target volume (ITV) rather than applying breathing margins might be worth considering.In conclusion, we believe there is something to be gained from assessing respiratory motion for each APBI patient. For most patients, a significant PTV margin reduction from the commonly used 5 mm to 0–2 mm could be justifiable, especially in the medial–lateral direction. Patients with larger or nonrigid motion needing special management can be identified. Intratreatment monitoring is advisable. Further study is needed of interfraction consistency of motion, the correlation of bony and surface surrogates with the target, and the dosimetric impact of using different margins. Similar approaches may be considered for breast boost treatments. Even the few patients evaluated in our clinic exhibit the range of observed motion in the literature and the approaches one might take to address it (Figs. 2, 3, and 4).Fig. 2Magnitude of individual marker motion over a breathing cycle in a patient with relatively large, uniform respiratory motion (∼7 mm) consistent with the largest motions reported in the literature (Table).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 3Magnitude of individual marker motion over a breathing cycle in a patient with relatively small motion, consistent with most studies using four-dimensional computed tomography or fluoroscopic imaging of internal markers.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig. 4Magnitude of individual marker motion over a breathing cycle in a patient with non-uniform target motion, a phenomenon also observed by Lee et al. (2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Although toxicity associated with external-beam accelerated partial breast irradiation (APBI) has been reported to be acceptable in some studies, others have shown higher rates of fibrosis and suboptimal cosmesis using the fractionation schedule of 385 cGy twice daily to 3850 cGy. Given that this fractionation schedule may be close to the limits of normal tissue toxicity, any reduction in irradiated normal tissue volume that can be achieved without compromising target coverage may have meaningful clinical significance. Recent studies have explored the use of image guidance to reduce the planning target volume (PTV) margin required to accommodate setup errors. There have also been many recent studies of respiratory motion in patients treated with APBI in the supine position (1Baglan K.L. Sharpe M.B. Jaffray D. et al.Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).Int J Radiat Oncol Biol Phys. 2003; 55: 302-311Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar, 3Becker S.J. Patel R.R. Mackie T.R. 4DCT intrafraction motion margin assessment in breast cancer treatments [abstract].Radiother Oncol. 2005; 76: S74Abstract Full Text PDF Google Scholar, 4Ahn S. Analysis of breast motion with 4 dimensional computerized tomography simulator [abstract].Int J Radiat Oncol Biol Phys. 2006; 66: S230-S231Abstract Full Text Full Text PDF Google Scholar, 5Bert C. Metheany K.G. Doppke K.P. et al.Clinical experience with a 3D surface patient setup system for alignment of partial-breast irradiation patients.Int J Radiat Oncol Biol Phys. 2006; 64: 1265-1274Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 6Chopra S. Dinshaw K.A. Kamble R. Sarin R. Breast movement during normal and deep breathing, respiratory training and set up errors: implications for external beam partial breast irradiation.Br J Radiol. 2006; 79: 766-773Crossref PubMed Scopus (41) Google Scholar, 7Morrow N.V. Stepaniak C. White J. Wilson J.F. Li X.A. Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 69: 910-917Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar, 9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar, 10Park C.K. Zhang G. Forster K.M. Harris E.E.R. Evaluation of fiducial marker migration and respiratory-induced motion for image guided radiotherapy in accelerated partial breast irradiation [abstract].Int J Radiat Oncol Biol Phys. 2009; 75: S626-S627Abstract Full Text Full Text PDF PubMed Google Scholar, 11Penninkhof J. Quint S. de Boer H. et al.Surgical clips for position verification and correction of non-rigid breat tissue in simultaneously integrated boost (SIB) treatment.Radiother Oncol. 2009; 90: 110-115Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 12Price G.J. Sharrock P.J. Marchant T.E. et al.An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.Phys Med Biol. 2009; 54: 6515-6533Crossref PubMed Scopus (20) Google Scholar, 13Lee R. Suh H. Surgical clips for observation of respiratory motion of the breast via 2D fluoroscopy and 3D CT scans.J Korean Phys Soc. 2010; 56: 1852-1860Crossref Scopus (1) Google Scholar, 14Liao Z.W. Guan X.X. Li F.Y. et al.Accelerated partial breast irradiation: use of four-dimensional CT for target localization and assessment of intrafractional motion.Oncol Res. 2010; 18: 503-507Crossref PubMed Scopus (12) Google Scholar, 15Qi X.S. White J. Rabinovitch R. et al.Respiratory organ motion and dosimetric impact on breast and nodal irradiation.Int J Radiat Oncol Biol Phys. 2010; 78: 609-617Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 16Yue N.J. Goyal S. Zhou J. Khan A.J. Haffty B.G. Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.Int J Radiat Oncol Biol Phys. 2011; 79: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 18Bedi C. Kron T. Willis D. Hubbard P. Milner A. Chua B. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging.Clinical Oncology. 2011; 23: 601-607Abstract Full Text Full Text PDF Scopus (15) Google Scholar, 19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar), and it may be time to reevaluate the PTV margin required to accommodate respiratory motion as well. The 19 studies summarized in the following table report a wide range of target motion that, at its extremes, spans a whole order of magnitude. Harris et al. (19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar) reported the use of four-dimensional computed tomography (4D-CT) to track gold fiducial markers placed at the periphery of the surgical bed in 15 patients and found that “the average intrafraction respiration induced fiducial motion was 0.8 mm.” By contrast, Yue et al. reported an average CTV motion of 8.5 mm in 4D-CTs of 4 APBI patients (8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar). Of the 19 studies, the “take-home” motion magnitude was <2 mm in five studies, 2 to 4 mm in 10 studies, and >5 mm in 4 studies. Abbreviations: CT = computed tomography; Max = maximum; SD = standard deviation; 1D = one-dimensional; 4D = four-dimensional. One early study on the larger end of the spectrum is that by Baglan et al. (1Baglan K.L. Sharpe M.B. Jaffray D. et al.Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT).Int J Radiat Oncol Biol Phys. 2003; 55: 302-311Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). Evaluating surgical clip positions in CTs of 16 patients acquired at normal inspiration and expiration breath-holds, they reported a mean motion of 6 mm (range, 3–9 mm). From this, they suggested that “a conservative margin of 5 mm around the CTV would completely account for breast motion during quiet respiration in all patients.” (Note that if a target is localized to its midventilation position, a symmetric breathing margin encompasses twice its value in target motion. In this case, a 5-mm symmetric margin was chosen to accommodate a potential 1-cm excursion.) Adding another 5-mm margin to account for setup error, Baglan et al. obtained a 1-cm PTV margin that has since been widely adopted and is part of the NSABP B-39/RTOG 0413 protocol. However, as seen above, most subsequent studies have reported target motions under 4 mm. This suggests that for most patients, the breathing component of the PTV margin can be reduced to ∼2 mm. If a dosimetric margin (as opposed to a full-range margin) is applied, the margin could be even smaller, although this has not been specifically demonstrated for partial breast radiotherapy. A margin reduction from 5 mm to 0–2 mm is significant and similar to the reduction that can be achieved with image guidance to reduce setup errors. Further reduction might be achieved by using nonuniform margins. Although a few studies have observed significant lateral respiratory motion of the target (2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar, 8Yue N.J. Li X. Beriwal S. Heron D.E. Sontag M.R. Huq M.S. The intrafraction motion induced dosimetric impacts in breast 3D radiation treatment: a 4DCT based study.Med Phys. 2007; 34: 2789-2800Crossref PubMed Scopus (32) Google Scholar, 9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar), most have reported motion primarily in the anterior–posterior and superior–inferior directions (4Ahn S. Analysis of breast motion with 4 dimensional computerized tomography simulator [abstract].Int J Radiat Oncol Biol Phys. 2006; 66: S230-S231Abstract Full Text Full Text PDF Google Scholar, 11Penninkhof J. Quint S. de Boer H. et al.Surgical clips for position verification and correction of non-rigid breat tissue in simultaneously integrated boost (SIB) treatment.Radiother Oncol. 2009; 90: 110-115Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 13Lee R. Suh H. Surgical clips for observation of respiratory motion of the breast via 2D fluoroscopy and 3D CT scans.J Korean Phys Soc. 2010; 56: 1852-1860Crossref Scopus (1) Google Scholar, 14Liao Z.W. Guan X.X. Li F.Y. et al.Accelerated partial breast irradiation: use of four-dimensional CT for target localization and assessment of intrafractional motion.Oncol Res. 2010; 18: 503-507Crossref PubMed Scopus (12) Google Scholar, 16Yue N.J. Goyal S. Zhou J. Khan A.J. Haffty B.G. Intrafractional target motions and uncertainties of treatment setup reference systems in accelerated partial breast irradiation.Int J Radiat Oncol Biol Phys. 2011; 79: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). At our institution, we have acquired 4D-CTs in patients receiving APBI (n = 8) with gold fiducial markers sutured to the walls of the lumpectomy cavity. In these patients, the maximum marker motion varied by an order of magnitude (range, 0.7–7.5 mm), but the maximum lateral motion out of all markers in all patients was 1.5 mm. On the basis of such data, nonuniform margins might be considered to reduce the irradiated volume in the medial–lateral direction. Although evidence suggests that margins may be safely reduced in most patients, the evidence for reducing margins for all patients is less firm. Any effort to reduce margins should therefore be accompanied by individual assessments of respiratory motion for each patient. In particular, it is important to be able to identify those patients on the tail end of the distribution that exhibit large breathing motion. Given the disagreement in the literature, it is not clear what proportion of the patient population this may represent. As mentioned above, an average motion >5 mm was seen in four of the studies cited here, but a greater number of studies did not report even a single patient moving >5 mm. (The remainder reported motion >5 mm at the top of their range, although the averages were lower. Of our eight patients, three exceeded 5 mm, and our mean was 4 mm.) The AAPM TG-76 report recommends management of respiratory motion exceeding 5 mm. In practice, such patients should not be hard to identify in a clinic equipped with fluoroscopy or 4D-CT or other respiratory tracking capability. If patient-specific assessment of respiratory motion is used, it will be important to verify the consistency of a patient’s breathing between simulation and treatments. Harris et al., Park et al., and Afghan et al. have all reported on multiple sessions of respiratory motion measurement (9Afghan M.K.N. Ye J.-S. Wong T.P. et al.Real-time lumpectomy cavity motion during external beam accelerated partial breast irradiation [virtual poster]. ASTRO 2009 Virtual Poster Library [web site]. American Society for Therapeutic Radiology and Oncology, Fairfax, VA2009http://astro2009.abstractsnet.com/aposter.wcs?entryid=060902Google Scholar, 10Park C.K. Zhang G. Forster K.M. Harris E.E.R. Evaluation of fiducial marker migration and respiratory-induced motion for image guided radiotherapy in accelerated partial breast irradiation [abstract].Int J Radiat Oncol Biol Phys. 2009; 75: S626-S627Abstract Full Text Full Text PDF PubMed Google Scholar, 19Harris E. Prtiz J. Latifi K. Zhang G. Forster K. Fiducial based image guided radiotherapy for whole breast irradiation [abstract].Radiother Oncol. 2011; 99: S300Abstract Full Text PDF PubMed Google Scholar). In the first two studies, 4D-CTs were acquired at pretreatment simulation and at the end of treatment. Harris et al. reported that in 15 patients, “the average variation of respiratory motion pre- to post treatment was 0.0 mm (SD = 1.0 mm; range,−2.5 to 2.2 mm.)” Park et al. reported nearly identical results in 22 patients: “average variation in respiratory motion for individual fiducials was −0.1 mm (SD = 0.9 mm; range, −2.5 to 2.2 mm.)” By contrast, Aghan et al. reported that 2 patients with implanted electromagnetic transponders had respiratory motion ranges of 4.7 and 6.5 mm over seven and five fractions, respectively. Until this issue is better understood, intrafraction monitoring of patients with individualized respiratory margins is advisable. Possible monitoring techniques include fluoroscopy, 4D cone-beam CT, electromagnetic transponders, and surface tracking. The latter two have the advantage of not adding radiation dose to the patient, permitting continuous monitoring throughout treatment. However, surface imaging does not track target motion directly, nor does fluoroscopy in the absence of fiducial markers. Although some studies have relied on surrogates for the target, the relationship between surrogate and target motion is not well established. Becker et al. analyzed multiple features such as the surface, the chest wall, and the anterior and posterior edges of the cavity, but their abstract does not give results beyond noting that all observed motions were <2.5 mm (3Becker S.J. Patel R.R. Mackie T.R. 4DCT intrafraction motion margin assessment in breast cancer treatments [abstract].Radiother Oncol. 2005; 76: S74Abstract Full Text PDF Google Scholar). Kirby et al. (17Kirby A.M. Evans P.M. Helyer S.J. et al.A randomised trial of supine versus prone breast radiotherapy (SuPr study): comparing set-up errors and respiratory motion.Radiother Oncol. 2011; 100: 221-226Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) and Bedi et al. (18Bedi C. Kron T. Willis D. Hubbard P. Milner A. Chua B. Comparison of radiotherapy treatment plans for left-sided breast cancer patients based on three- and four-dimensional computed tomography imaging.Clinical Oncology. 2011; 23: 601-607Abstract Full Text Full Text PDF Scopus (15) Google Scholar) reported comparable motion of clips and chest wall, a finding that might be relevant in fluoroscopic verification. We can report that in our 8 patients, the magnitude of maximum nipple displacement and maximum individual clip displacement agreed in all patients within 2 mm. On average, the nipple underestimated maximum marker motion by 0.4 mm (SD, 1.1 mm). Also, a midline BB may be taken as a surrogate for the sternum, which can be tracked under fluoroscopy. In our patients, the BB underestimated the maximum marker motion by an average of 0.4 mm (SD, 1.1 mm), with a maximum discrepancy of 2.3 mm. Many studies have evaluated patients with multiple fiducial markers and reported average or maximum motion. One study by Lee et al. (2Lee R, Suh H, Moon B, et al. Evaluation of breast motion as assessed by breast clips during normal breathing. In: Yi BY, Ahn SD, Choi EK, et al., editors. Proceedings of the XIVth International Conference on the Use of Computers in Radiation Therapy; 2004 May 10-13; Seoul, South Korea. Seoul: Jeong; 2004. p. 442–444.Google Scholar) presented fluoroscopic motion data for every marker they imaged (23 surgical clips in 7 patients). Their data show a difference of as much as 5 mm in the excursion of different clips in the same patient. Different parts of the target can move differently. A possibly related finding is reported by Price et al., (12Price G.J. Sharrock P.J. Marchant T.E. et al.An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.Phys Med Biol. 2009; 54: 6515-6533Crossref PubMed Scopus (20) Google Scholar) who observed in 12 patients that the lateral and, in some cases, superior parts of the breast surface moved more than the medial part, a finding corroborated by Morrow et al. (7Morrow N.V. Stepaniak C. White J. Wilson J.F. Li X.A. Intra- and interfractional variations for prone breast irradiation: an indication for image-guided radiotherapy.Int J Radiat Oncol Biol Phys. 2007; 69: 910-917Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). Of our patients, 2 had individual clips whose motion magnitudes differed as much as 2–3 mm from each other. Unlike Price et al., when we observed differences in individual clip motion, it was always the most superior markers that moved the least. One other patient showed considerably more nonrigid target motion. Between inhalation and exhalation, the anterior–superior markers moved approximately 1 mm, whereas the other markers moved as much as 6 mm (Fig. 1). For such a patient, creating an internal target volume (ITV) rather than applying breathing margins might be worth considering. In conclusion, we believe there is something to be gained from assessing respiratory motion for each APBI patient. For most patients, a significant PTV margin reduction from the commonly used 5 mm to 0–2 mm could be justifiable, especially in the medial–lateral direction. Patients with larger or nonrigid motion needing special management can be identified. Intratreatment monitoring is advisable. Further study is needed of interfraction consistency of motion, the correlation of bony and surface surrogates with the target, and the dosimetric impact of using different margins. Similar approaches may be considered for breast boost treatments. Even the few patients evaluated in our clinic exhibit the range of observed motion in the literature and the approaches one might take to address it (Figs. 2, 3, and 4).