Accelerated Partial Breast Irradiation Techniques and Clinical Implementation - part 10 doc

Normal Tissue Toxicity after Accelerated Partial Breast Irradiation 17.5.1 Toxicity Avoidance Guidelines As noted, the actual clinical toxicity data on 3D conformal external beam APBI

David E Wazer

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cised tissue, tumor diameter, and a history of diabetes or hypertension were not found

to be significantly associated with either cosmetic score or normal tissue toxicity In trast, several implant-associated variables could be identified as having significant influ-ence on the risk of an adverse cosmetic outcome or increased risk of late skin toxicity, late subcutaneous toxicity, and clinically evident fat necrosis (Table 17.3) (Wazer et al 2006) In general, the volume of the implant, the volume of dose “hotspots” as defined by the V150 and V200, and the global dose homogeneity of the implant as described by the DHI were strongly correlated with adverse outcome This study was the first to provide some specific dosimetric parameters to guide clinicians in defining, at least with respect

con-to late tissue effects, what constitutes an optimal interstitial HDR implant

17.3.3 Is there an Adverse Interaction between Interstitial Brachytherapy and Chemotherapy?

The answer is “possibly” The first evidence presented in this regard was reported by Kuske et al (2002) from the RTOG 95-17 trial In their study, grade 3 toxicity was sig-nificantly increased with the use of chemotherapy This was true for both HDR and LDR techniques, but particularly so for LDR implants Similarly, Arthur et al (2003) found that APBI with an LDR interstitial technique was associated with a significant decrement

in cosmetic outcome when patients also received Adriamycin-based chemotherapy In the combined Tufts/Brown/VCU series (Wazer et al 2006) of HDR interstitial brachy-therapy, the use of Adriamycin-based chemotherapy was associated with an increased risk of clinically evident fat necrosis, grade 1/2 skin toxicity, and suboptimal cosmetic scores In contrast, no adverse interactive effect has yet been found between the use of chemotherapy and the MammoSite catheter (Vicini et al 2005)

17.3.4 Toxicity Avoidance Guidelines

As clinical data continue to accumulate, toxicity avoidance guidelines can, at best, be considered preliminary and subject to future revision The guidelines that will be put forward are, by and large, limited to the use of HDR interstitial brachytherapy To date, the amount and dosimetric specificity of data regarding LDR implants is simply too sparse to make even limited recommendations With these caveats, current data do sug-gest the following:

constraints imposed by adequate coverage of the PTV Ideally, less than 60% of the normal whole breast reference volume should receive greater than or equal to 50% of the prescribed dose

sensi-tive in this regard is the V150 Most certainly, this value needs to be ≤70 cm3 though

it appears preferable to strive for <45 cm3

at least >0.75, even better >0.85 This is achievable with all of the common currently employed interstitial catheter placement techniques but does require attention to the detail of catheter position

17 Normal Tissue Toxicity after Accelerated Partial Breast Irradiation 

the dose delivered to these structures should be less than the prescribed dose eate the PTV such that it is at least 5 mm from the skin

APBI

17.4 MammoSite Brachytherapy

The first and perhaps most critical factor to consider in assessing risk of normal tissue effects with MammoSite brachytherapy is that, from the perspective of both dosimetry and radiobiology, it is a distinctly different implant from interstitial brachytherapy As such, one must be cautious in transferring the lessons learned from interstitial brachy-therapy APBI as they likely have limited relevance to this applicator system As an ex-ample of these inherent differences, Shah et al (2004) reported a series of interstitial and MammoSite implants and found significant differences in critical dosimetric pa-rameters MammoSite implants are associated with significantly less irradiated tissue and smaller volume “hotspots” as compared to interstitial brachytherapy (for example,

V150 of 26 cm3 with MammoSite vs 40 cm3 with interstitial technique, P<0.0001) In

contrast, the global uniformity as reflected in the calculated DHI is superior with an interstitial implant (DHI of 0.83 with interstitial technique vs 0.73 with MammoSite,

P<0.0001) The relative importance of these variables in predicting normal tissue toxicity

after MammoSite brachytherapy has yet to be fully elucidated

In addition to the standard toxicity endpoints as described in the RTOG/EORTC ing scale, there are events that are, for the most part, specific to the MammoSite catheter that can result in implant failure These include:

The initial safety and performance multi-institutional trial of the MammoSite eter was performed by Keisch et al (2003) This study of 43 patients investigated acute toxicity encountered up to 4 weeks after treatment The most common side effects of the procedure included mild erythema (57.4%), drainage (51.9%), pain (42.6%), ecchymosis (31.5%), seroma (11.1%), and an infection rate of 3.7% (Figs 17.9 and 17.10) Post-pro-cedure infections have been the focus of some controversy in the early experience with the MammoSite catheter (Harper et al 2005) However, it does appear that with meticu-lous wound care during the 1–2 weeks required to complete irradiation, the infection rate can be kept acceptably low even when assessed amongst a broad base of users In a report of the American Society of Breast Surgeons (ASBS) Breast Brachytherapy Regis-try trial, the device-related infection rate among 793 patients was only 5.9% (Vicini et al 2005) Prophylactic antibiotic use is advocated by some (Harper et al 2005), but its role

cath-in modifycath-ing the rate of device-related cath-infections remacath-ins unclear

The incidence of seroma after MammoSite APBI is another area of on-going study (Fig 17.11) The acute incidence of 11% reported by Keisch et al (2003) likely under-represents the frequency of persistent asymptomatic and symptomatic seroma seen

David E Wazer

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Fig 17.5 An example of unacceptable

non-con-formance to target breast tissue of the fully inflated

MammoSite catheter

Fig 17.6 Intracavitary hemorrhage 24 hours after intraoperative placement of a MammoSite cath- eter

Fig 17.7 Spontaneous rupture of a MammoSite

catheter 48 hours after placement results in partial

filling of the lumpectomy cavity with dilute

con-trast material

Fig 17.8 Suboptimal balloon-to-skin spacing after intraoperative MammoSite placement neces- sitating catheter removal

17 Normal Tissue Toxicity after Accelerated Partial Breast Irradiation 

after several months of follow-up The factors that contribute to the risk of persistent seroma as well as the most effective clinical management strategy have yet to be fully elucidated

As the MammoSite catheter was approved for clinical use in May 2002 by the United States Food and Drug Administration, few data exist on the intermediate and late tissue effects Keisch et al (2004) have reported on a more extended evaluation of their original

43 patient cohort with a median follow-up of 29 months These data show that cosmetic scores are clearly related to balloon-to-skin spacing such that suboptimal results are seen when the spacing is ≤6 mm Further, these authors report asymptomatic fat necrosis

in 4.9%, subcutaneous fibrosis in 29%, and telangiectasia in 27% In light of the dependent evolution of late effects reported with interstitial brachytherapy APBI by the Beaumont Hospital group (Fig 17.2), a reasonable expectation is that similar changes may be seen with further follow-up of the MammoSite experience

time-Additional data regarding intermediate and late effects on normal tissue after moSite APBI are being actively collected through the ASBS Registry trial (Vicini et al 2005) In a report of 702 patients, factors found to be significantly associated with favor-able cosmetic outcome are balloon-to-skin spacing, both as a continuous variable and at

Mam-a cut-off vMam-alue of ≥7 mm, Mam-and lMam-arger brMam-a size (C/D versus A/B) (Vicini et Mam-al 2005) The use of chemotherapy or tamoxifen was not found to adversely affect cosmetic outcome

Fig 17.11 Persistent and painful seroma (with

as-sociated mammogram) at the operative bed in the

upper outer quadrant 9 months after completion

of MammoSite brachytherapy APBI

Fig 17.9 An example of the severity of acute skin

affects that can be seen after MammoSite

brachy-therapy APBI: grade 3 skin reaction 5 weeks after

completion of treatment The balloon-to-skin

dis-tance was >9 mm

Fig 17.10 Infection in the operative bed 8 weeks after completion of MammoSite brachytherapy APBI

David E Wazer

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How do MammoSite and interstitial brachytherapy compare with respect to normal tissue side effects? One might expect that, with the smaller volume of irradiated tissue seen with MammoSite, that MammoSite would be clearly superior in this regard To ad-dress this question, Shah et al (2004) used an expanded dataset from the Tufts/Brown/VCU collaboration to perform a comparison of normal tissue toxicity encountered with interstitial brachytherapy (75 cases) versus MammoSite (28 cases) When all patients were included, the use of the MammoSite catheter was associated with a higher rate of

grade 1 acute skin toxicity (42.9% vs 17.3%, P= 0.01) whereas subcutaneous fibrosis was

more commonly seen with interstitial brachytherapy (32% vs 10.7%) However, when interstitial brachytherapy patients who received chemotherapy were excluded from the analysis (as none of the MammoSite patients received chemotherapy), the only signifi-cant difference that remained between the groups was a higher rate of grade 1 skin toxic-ity with MammoSite

17.4.1 Toxicity Avoidance Guidelines

As with interstitial brachytherapy, toxicity avoidance guidelines for use of the moSite catheter for APBI must be considered preliminary and subject to change with the emergence of longer term follow-up studies Nonetheless, based upon currently avail-able information, the following guidelines are offered:

Mam-moSite catheter placement Adherence to wound care instructions should result in a minimal rate (<5%) of device-related infections

17.5 3D Conformal External Beam APBI

The data available to assess normal tissue effects after 3D conformal external beam APBI are very limited and conclusions are, at best, preliminary One of the largest experiences reported to date is that from the William Beaumont Hospital (Baglan et al 2003; Vicini

et al 2003) where 31 patients were treated with 34 or 38.5 Gy in ten twice-daily tions After a median follow-up of 10 months, no significant immediate toxicity was seen beyond grade 1 skin erythema At 4–8 weeks of follow-up, only grade 1 and 2 toxicity was seen in 61% and 10%, respectively Cosmetic results were rated good or excellent

frac-in all patients with up to 2 years of follow-up These promisfrac-ing prelimfrac-inary data have lead to multi-institutional prospective phase II and phase III trials (RTOG 0319, RTOG 0413/NSABP B-39) to further test this approach

Formenti et al (2004) have used a conformal external beam partial breast tion technique with patients in the prone position In contrast to the Beaumont Hospital group, an even more extreme hypofractionation scheme was employed with 30 Gy at

irradia-6 Gy per fraction delivered in five fractions over 10 days In 47 patients with a median follow-up of 18 months, the normal tissue effects were found to be minor with nothing more than grade 1 acute or late toxicity

17 Normal Tissue Toxicity after Accelerated Partial Breast Irradiation 

17.5.1 Toxicity Avoidance Guidelines

As noted, the actual clinical toxicity data on 3D conformal external beam APBI is sparse and specific dose–volume relationships cannot yet be stated with confidence Nonethe-less, based upon the preliminary practice at William Beaumont Hospital (Baglan et al 2003; Vicini et al 2003), the following are suggested:

than or equal to 50% of the prescribed dose and less than 35% of the whole breast normal reference volume should receive the prescribed dose

point

dose As for left-sided lesions, acceptable dose–volume limits are still uncertain and are subject to further analysis of data accumulated in the phase II trial of 3D confor-mal external beam APBI (RTOG 0319)

dose

17.6 Intraoperative APBI

There are two intraoperative partial breast irradiation techniques currently under vestigation In Milan, Italy, Veronesi et al (2005) are testing an approach that employs 3–9 MeV electrons to deliver 21 Gy as a single fraction to the excision bed In a report

in-of 590 patients with a median follow-up in-of 20 months, the authors claim a low rate in-of complications They report mild to severe fibrosis in 3.2%, “that resolved in 24 months” Overt fat necrosis was seen in 2.5% of patients within 1–4 weeks after treatment.Another approach pioneered by Vaidya et al (2004) uses a device with a spherical tip that is inserted intraoperatively into the lumpectomy cavity A 50-kV x-ray beam is generated to deliver a single fraction of 5 Gy prescribed at 1 cm from the surface of the applicator A prospective randomized trial is underway in the United Kingdom and, to date, no normal tissue toxicity data are available

17.7 Conclusion

Current techniques of APBI differ markedly in their dosimetric and radiobiological properties As such, normal tissue toxicity data must be carefully collected in a prospec-tive fashion for each treatment modality and fractionation scheme Ongoing assessment

of both clinical and treatment-related factors that may contribute to adverse normal sue effects is required in order to minimize the risk of both early and late toxicity To date, our most complete understanding of the incidence and variables associated with normal tissue injury after APBI is based upon the experience with interstitial brachy-therapy and, to a lesser degree, the MammoSite catheter The general applicability of the lessons learned with these catheter systems to other APBI modalities must be ap-proached with caution

Baglan KL, Sharpe MB, Jaffray D, et al (2003) Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT) Int J Radiat Oncol Biol Phys 55:302–311

Benitez PR, Chen PY, Vicini FA, et al (2004) Partial breast irradiation in breast-conserving therapy by way of interstitial brachytherapy Am J Surg 188:355–364

Das RK, Patel R, Shah H, et al (2004) 3D CT-based high-dose-rate breast brachytherapy plants: treatment planning and quality assurance Int J Radiat Oncol Biol Phys 59:1224–1228 Edmundson GK, Vicini FA, Chen PY, et al (2002) Dosimetric characteristics of the MammoSite RTS, a new breast brachytherapy applicator Int J Radiat Oncol Biol Phys 52:1132–1139 Formenti SC, Minh TT, Goldberg JD, et al (2004) Prone accelerated partial breast irradiation after breast conserving surgery: preliminary clinical results and dose-volume histogram analy- sis Int J Radiat Oncol Biol Phys 60:493–504

im-Harper JL, Jenrette JM, Vanek KN, et al (2005) Acute complications of MammoSite apy: a single institution’s initial clinical experience Int J Radiat Oncol Biol Phys 61:169–174 Keisch M, Vicini F, Kuske RR, et al (2003) Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early stage breast cancer treated with breast conserving therapy Int J Radiat Oncol Biol Phys 55:289–293

brachyther-Keisch M, Vicini F, Scroggins T, et al (2004) Thirty month results with the MammoSite breast brachytherapy applicator: cosmesis, toxicity, and local control in partial breast irradiation Int

J Radiat Oncol Biol Phys 60 [Suppl]:272

King TA, Bolton JS, Kuske RR, et al (2000) Long-term results of wise-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer Am

J Surg 180:299–304

Kuerer HM, Julian TB, Strom EA, et al (2004) Accelerated partial breast irradiation after servative surgery for breast cancer Ann Surg 239:338–351

con-Kuske R, Bolton JS, McKinnon WP, et al (1998) Five-year results of a prospective phase II trial

of wide-volume brachytherapy as the sole method of breast irradiation in Tis, T1, T2, N0-1 breast cancer (abstract) Int J Radiat Oncol Biol Phys 42 [Suppl]:181

Kuske RR, Winter K, Arthur D, et al (2002) A phase II trial of brachytherapy alone following lumpectomy for select breast cancer: toxicity analysis of Radiation Therapy Oncology Group 95-17 Int J Radiat Oncol Biol Phys 54 [Suppl]:87

Lawenda BD, Taghian AG, Kachnic LA, et al (2003) Dose-volume analysis of radiotherapy for T1N0 invasive breast cancer treated by local excision and partial breast irradiation by low- dose-rate-interstitial implant Int J Radiat Oncol Biol Phys 56:671–680

Polgar C, Sulyok Z, Fodor J, et al (2002) Sole brachytherapy of the tumor bed after tive surgery for T1 breast cancer: five year results of a phase I-II study and initial findings of a randomized phase III trial J Surg Oncol 80:121–128

conserva-Polgar C, Major T, Fodor J, et al (2004) High dose rate brachytherapy alone versus whole breast radiotherapy with or without tumor bed boost after breast conserving surgery: seven year re- sults of a comparative study Int J Radiat Oncol Biol Phys 60:1173–1181

17 Normal Tissue Toxicity after Accelerated Partial Breast Irradiation 

Shah NM, Tennenholz T, Arthur D, et al (2004) MammoSite and interstitial brachytherapy for accelerated partial breast irradiation: factors that affect toxicity and cosmesis Cancer 101:727–734

Vaidya JS, Tobias JS, Baum M, et al (2004) Intraoperative radiotherapy for breast cancer cet Oncol 5:165–173

Lan-Veronesi U, Orecchia R, Luini A, et al (2005) Full-dose intraoperative radiotherapy with trons during breast-conserving surgery: experience with 590 cases Ann Surg 242:101–106 Vicini FA, Chen PY, Fraile M, et al (1997) Low-dose-rate brachytherapy as the sole radiation modality in the management of patients with early stage breast cancer treated with breast-con- serving therapy: preliminary results of a pilot trial Int J Radiat Oncol Biol Phys 38:301–310 Vicini FA, Kestin LL, Edmundson GK, et al (1999) Dose-volume analysis for quality assurance

elec-of interstitial brachytherapy for breast cancer Int J Radiat Oncol Biol Phys 45:803–810 Vicini FA, Remouchamps V, Wallace M, et al (2003) Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial breast irradiation in patients with early stage breast cancer treated with breast conserving therapy Int J Radiat Oncol Biol Phys 57:1247–1253

Vicini F, Beitsch P, Quiet C, et al (2005) First analysis of patient demographics, technical ducibility, cosmesis and early toxicity by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry trial in 793 patients treated with accelerated partial breast ir- radiation (APBI) Cancer 104:1138–1148

repro-Wazer DE, Kramer B, Schmid C, et al (1997) Factors determining outcome in patients treated with interstitial implantation as a radiation boost for breast conservation therapy Int J Radiat Oncol Biol Phys 39:381–393

Wazer DE, Kaufman S, Cuttino L, et al (2006) Accelerated partial breast irradiation: An sis of variables associated with late toxicity and long-term cosmetic outcome after high-dose- rate interstitial brachytherapy Int J Radiat Oncol Biol Phys 64:489–495

analy-Wu A, Ulin K, Sternick E (1988) A dose homogeneity index for evaluating Ir-192 interstitial breast implants Med Phys 15:104–107

Future Directions: Phase III

Cooperative Group Trials

Joseph R Kelley and

Douglas W Arthur

18

18.1 Introduction

Through the past 15 years, several single-institutional trials in Europe and the United States have been published with results that maintain that the use of accelerated par-tial breast irradiation (APBI) yields acceptable toxicity and comparable local control to standard breast-conservation therapy with whole-breast irradiation (WBI) (Arthur et al 2003; King et al 2000; Lawenda et al 2003; Polgar et al 2002; Vicini et al 2003; Wazer et

al 2002) The follow-up periods in these trials range from 3 to >5 years and the numbers

of patients included in these trials amount to a combined experience of several hundred patients These trials have helped to provide the needed data to allow initial definition of patient selection criteria and the development of basic rules for treatment delivery and quality assurance for those physicians who choose to offer APBI in their clinical practice (American Society of Breast Surgeons 2005; Arthur 2003; Arthur et al 2002) However,

it must be recognized that the concept of APBI challenges the present standard treat-ment paradigm for early-stage breast cancer and introduces new treattreat-ment concepts that include target volume reduction to a partial breast target and the intensification of the treatment fractionation scheme to deliver the total dose in 5 days To fully understand the impact of these new concepts and the role of APBI in the management of early-stage breast cancer, additional data are needed This additional information can only be obtained through properly designed clinical trials and a joint effort by all physicians in supporting these trials

Contents

18.1 Introduction 263

18.2 Patient Selection/Study Eligibility 266

18.3 Target Delineation 267

18.4 Technique and Dosimetry 269

18.5 Quality Assurance 271

18.6 Conclusion 271

References 272

Joseph R Kelley and Douglas W Arthur

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Presently two large, multi-institutional phase III clinical trials are actively accruing, one in Europe and one in the United States They are both designed to definitively com-pare APBI with WBI in a prospective randomized fashion and to further define the role

of APBI in the management of early-stage breast cancer The European Brachytherapy Breast Cancer GEC-ESTRO (Groupe Européen de Curietherapie–European Society for Therapeutic Radiology and Oncology) Working Group has opened a multicenter phase III trial, potentially including 12 institutions from seven European countries, with a goal

of randomizing 1170 women between standard WBI and APBI utilizing multicatheter brachytherapy, see Fig 18.1 (Strnad and Polgar 2004) This trial has been statistically designed as a noninferiority trial With the patient accrual goal of 1170, the study is powered with a significance level set to 0.05 to detect greater than the set non-relevant 3% increase in local failure rate above the 5-year in-breast failure reference value of 4%

If the local failure rate in the APBI arm does not exceed 7%, then APBI will be judged to

be “non-inferior” to adjuvant WBI

Fig 18.1 GEC-ESTRO multicenter phase III trial (HDR-BRT high dose-rate brachytherapy, PDR-BRT

pulsed dose-rate brachytherapy)

The National Surgical Adjuvant Breast and Bowl Project (NSABP) jointly with the Radiation Therapy Oncology Group (RTOG) subsequently opened a 3000-patient phase III trial in the United States This trial will also compare standard whole-breast radio-therapy to APBI utilizing multicatheter brachytherapy, MammoSite balloon brachyther-apy or the three-dimensional conformal external beam (3D-CRT) technique (Fig 18.2)

18 Future Directions: Phase III Cooperative Group Trials 

(Vicini et al 2004) This trial is statistically designed as a trial of equivalence Based

on previous NSABP trial data, the estimated 10-year cumulative incidence of in-breast recurrence is 6.1% for the population to be included in this trial and an acceptable vari-ance from this result set as ±3% If the risk of in-breast tumor recurrence following APBI relative to the risk of in-breast tumor recurrence following WBI is ≥1.5, then APBI will

be defined as inferior to WBI If the risk of in-breast tumor recurrence following APBI relative to the risk of in-breast tumor recurrence following WBI is ≤1/1.5 (0.667), then WBI will be defined as inferior to APBI If neither APBI is inferior to WBI nor WBI inferior to APBI, then APBI will be defined as equivalent to WBI

Fig 18.2 NSABP B39/RTOG 0413 protocol schema

The primary objective in both trials is to determine if local control is equivalent tween APBI and WBI Secondary objectives are also similar in that acute and late toxici-ties will be reviewed, cosmetic outcome compared, quality of life differences evaluated and failure patterns including distant metastases-free survival, disease-free survival and overall survival assessed The key components of successful partial breast irradiation are patient selection, target delineation, technique, dosimetry, and quality assurance These components are clearly outlined in the European phase III trial (GEC-ESTRO multi-center phase III trial) and the American phase III trial (NSABP B-39/RTOG 0413) In review of these trials, many similarities are appreciated, subtle differences are seen and