14 New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation

Chapter

New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation

Mark J. Rivard, Alphonse G.

Taghian and David E. Wazer

14

14.1 APBI: Established, New, and Novel Approaches

Many of the other chapters in this text discuss in detail the established techniques for APBI delivery with significant attention given to techniques specific to certain institu- tions. Furthermore, some chapters stress the cohesion of established techniques through multi-institutional clinical trials and implementation of uniform quality assurance prac- tices. However, this chapter focuses on the possible directions for the future of APBI by looking at new and novel approaches to APBI delivery.

There are recent publications (see for example Hui and Das 2005, Formenti et al.

2004, or Butler and Butler 2005) in which patient positioning (prone or decubitus vs.

conventional supine) are important improvements to established approaches. While quite useful in some cases, alteration of patient set-up alone does not satisfy the defini- tion for a new or novel APBI treatment modality. Creative efforts should focus on de- velopments of the treatment delivery system. Small but required steps forward from low dose-rate (LDR) 60Co or 192Ir temporary implants (Fourquet et al. 1995; Póti et al. 2004) would be the use of alternative brachytherapy radionuclides (e.g., high dose-rate, HDR, 169Yb, 170Tm, or 171Tm) or the use of permanent LDR seed implants such as 103Pd or 125I. Application of other esoteric brachytherapy delivery systems to APBI would follow.

In a similar context, utilization of teletherapy systems for APBI such as 3D conformal

14.1 APBI: Established, New, and Novel Approaches . . . 197

14.2 Teletherapy . . . 198

14.2.1 Proton Teletherapy for APBI . . . 199

14.3 Brachytherapy . . . 201

14.3.1 Seeds Containing Radionuclides . . . 202

14.3.2 Microbrachytherapy . . . 202

14.3.3 Electronic Brachytherapy . . . 203

14.4 Summary . . . 204

References . . . 205

Mark J. Rivard, Alphonse G. Taghian and David E. Wazer

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radiation therapy (3D-CRT) protons or intensity-modulated radiation therapy (IMRT) protons would offer increasing levels of complexity, yet potential for improved treatment delivery.

While one could consider using almost any new treatment modality for APBI, it is necessary to delineate what desirable features these modalities should have, and how they should improve upon the established techniques:

• Capability for the current team of care providers (surgeons, oncologists, radiation oncologists) to use the modality in a cost-effective and time-sensitive manner with ease-of-use

• Ability to deliver therapy in a controlled manner which may be quantitatively con- firmed through measurements and calculations

• Provide therapy with improved homogeneity, conformity (non-target tissue sparing), and patient-specific compatibility

The majority of the new and/or novel approaches listed in the following sections have some or all of these desirable features. As these approaches to APBI may be categorized as to whether or not the therapy source emanates external to or within the patient, the following two sections are divided into teletherapy and brachytherapy, respectively.

14.2 Teletherapy

Conventional 3D-CRT for APBI is performed, but offers limited prospects due to the need to minimize irradiation of healthy breast tissues which limits forward treatment planning. IMRT with teletherapy photons has been used for the treatment of breast can- cer since the mid-1990s. With this treatment modality, smaller planning target volumes (PTVs) may be obtained as compared to those available from CRT. While IMRT for APBI has been used now for over a decade, therapy delivery using the fraction schema common to current APBI approaches (e.g., 3.4 Gy/fraction, twice daily, total 34 Gy) has only recently been examined (Coles et al. 2005).

Intraoperative radiation therapy (IORT) has been used in general for radiotherapy since the 1960s. However, application to breast treatment has been limited. Further fo- cusing of IORT to APBI, with its smaller clinical target volume (CTV) and decreased fractionation treatment schedule is discussed in Chapter 12. Herskind et al. (2005) have proposed using a spherical 50 kV x-ray source for single-dose or hypofractionated par- tial-breast IORT. The well-established LQ model was modified to determine the relative biological effectiveness as a function of dose, distance, and irradiation time for late-re- acting normal tissues and tumor cells. The calculated relative biological efficiency (RBE) for late reactions was near unity at the applicator surface, but increased with increasing distance (lower dose rates). Furthermore, the RBE for tumor cells was favorably calcu- lated to be larger than for late-reacting normal tissues. These factors provide the theo- retical basis for IORT for APBI.

In contrast to photons, particles with mass such as electrons, neutrons, or exotic par- ticles have not been utilized for APBI. Electrons have been used for recurrent disease (McKenzie et al. 1993; Nicolato and Franchini 1990), but not specifically for APBI. Mur- ray et al. (2005) and Halpern et al. (1990) have used neutrons for irradiation of locally advanced breast cancer, but not for partial breast treatment or in an accelerated fashion.

However, protons have been used recently and exhibit promise for APBI.

14. New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation 

14.2.1 Proton Teletherapy for APBI

Protons have physical and radiobiological characteristics which differ from those of con- ventional radiotherapy (photons), and offer a number of theoretical advantages. Dose localization in the Bragg peak provides an ideal characteristic for dose conformation to the target volume, and at the same time reduced dose to non-target tissues (Koehler et al. 1972). This unique dosimetric feature of proton teletherapy makes it an attractive non-invasive modality. The main critical indications are proximity of the target area to critical structures where maximum selectivity of dose distribution is of paramount im- portance. A general review of proton teletherapy is provided by Orecchia et al. (1998), who have demonstrated success in the treatment of diseases such as uveal melanoma, base of skull chordoma and chondrosarcoma, central nervous system, soft-tissue sar- coma, and prostate cancer. However, the use of proton teletherapy for breast cancer has been very limited.

At Massachusetts General Hospital in Boston, Taghian and colleagues initiated an IRB-approved phase I/II clinical trial to evaluate the safety and feasibility of using a sim- ple 3D-CRT APBI technique where the patient lies supine and treatment is delivered us- ing either proton teletherapy or a three-field photon beam arrangement including an en face electron field. Use of protons was based on preliminary study suggesting superiority of proton dose distribution when compared with IMRT or 3D-CRT using photons and electrons (El-Ghamry et al. 2002). Figure 14.1 shows dose distribution comparisons be- tween 3D-CRT photons, IMRT photons, and protons with the dose–volume histograms (DVHs) illustrating a 50% decrease in the dose received by the non-target breast tissue in favor of protons.

Fig. 14.1

Comparison of three treatment plans.

A Non-target breast tissue DVHs for 3D-CRT, IMRT, and proton treatment plans. At the 50%

isodose, there is improvement of approximately a factor of two going from 3D-CRT to protons, with IMRT falling somewhere in the middle. B Isodose lines for the same three treatment plans. It is clear that the proton teletherapy treatment plan, in com- parison to 3D-CRT or IMRT, offers much more conformal targeting and minimizes the dosage to healthy tissue (from Taghian et al. 2005)

B

Mark J. Rivard, Alphonse G. Taghian and David E. Wazer

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A summary of the clinical experience has been provided by Taghian et al. (2006).

From May 2004 to June 2005, 25 patients were treated with proton-based APBI. Eli- gibility criteria included: invasive carcinoma of <2 cm; negative sentinel node; margin width >2 mm; and no lymphovascular invasion. The excision cavity represented the CTV, which was expanded by 1.5–2.0 cm to create the PTV, and then edited so the PTV came no closer than 5 mm to the skin surface and no deeper than the anterior chest wall or pectoralis muscles. The prescribed dose was 32 Gy in eight fractions, delivered twice daily over 4 days. One to three fields were used as necessary to keep dose inhomogene- ity across the PTV less than 10%. Skin sparing with protons was less than that with photons, but was improved by the use of multiple fields. All 25 patients were treated with proton therapy. For 24 of them, a 3D plan using photon minitangents and an en face electron field was also generated. Dosimetric comparisons were made between pho- ton/electron plans and proton plans using paired t-tests (Kozak et al. 2006). Figure 14.2 illustrates a plan using standardized 3D-CRT photons and electrons versus two proton fields (Taghian et al. 2006). Notice the difference in the dose received by the non-target breast tissue.

Fig. 14.2

Treatment plans for proton teletherapy (left) and 3D-CRT using photons and electrons (right).

The dose to the chest wall, non-target breast, and lung are greatly minimized with proton teletherapy

Results for the first 25 patients showed that the median tumor size was 0.8 cm (range

0.2–1.8 cm). Fourteen patients had left-sided and eleven patients right-sided breast can-

cers. The median CTV was 19 cm3 (range 5–60 cm3) and the median PTV was 147 cm3

(range 46–307 cm3). The median percentage of the whole breast designated as PTV was

19% (range 7–37%). The mean doses delivered to the ipsilateral lung, heart, and non-

target breast (whole breast minus PTV), for both proton and photon/electron plans are

listed in Table 14.1. The use of protons resulted in lower doses to each of these normal

structures. PTV coverage for both modalities was equivalent. The volume of non-target

breast tissue receiving 50% of the dose (16 Gy) was 41% and 26% for photons/electrons

and proton treatment, respectively (P=0.0001).

14. New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation 

Proton-based APBI treatments are technically feasible, and intensity modulation us- ing protons may be even more promising. When compared to conventional 3D-CRT APBI treatments, doses delivered to normal structures such as the ipsilateral and contra- lateral lungs, heart, and non-target breast tissue were significantly lower without com- promising PTV coverage. Proton therapy will soon become more readily available as two new facilities are under construction in Houston and Florida (Particle Therapy Co-Op- erative Group 2005), and may become an attractive tool for APBI. Furthermore, the cost estimate suggest that proton used in APBI may actually be less expensive than invasive techniques (Mammosite and interstitial HDR implants) (Taghian et al 2006). However, studies are needed on its long-term effect on cosmetic outcome and late normal-tissue complications.

14.3 Brachytherapy

While brachytherapy for APBI is well-established using temporary implants with con- ventional radionuclides such as 60Co and 192Ir, novel brachytherapy systems for APBI are being researched. The following summarizes three areas in which interstitial treatments for APBI are being investigated.

Table 14.1

Doses to lung, heart, and non-target breast illustrating significant improvements using 3D- CRT protons in favor of photons and electrons

3D CRT photons/

electrons

3D-CRT protons P-value

Ipsilateral lung

Maximum dose (Gy) 28 19 0.001

Mean dose (Gy) 1.0 0.5 0.0001

D20 (Gy) 1.2 0.0 0.0001

D10 (Gy) 2.4 0.6 0.0001

D5 (Gy) 4.2 2.8 0.005

Heart

Maximum dose (Gy) 3.2 0.8 0.0001

Mean dose (Gy) 0.4 0.1 0.002

D20 (Gy) 0.5 0.0 0.002

D10 (Gy) 0.7 0.0 0.002

D5 (Gy) 1.0 0.0 0.002

Non-target breast

V16 Gy (%) 41 26 0.0001

D20, D10, D5 dose (Gy) received by 20%, 10% and 5% of the tissue

V16 Gy (%) percent of volume receiving 50% of the prescribed dose (i.e. 16 Gy)

Mark J. Rivard, Alphonse G. Taghian and David E. Wazer

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14.3.1 Seeds Containing Radionuclides

Unlike the conventional approach to use temporary implants, there is interest in perma- nently implanting brachytherapy sources at the time of lumpectomy. Due to their long half-lives of 5.27 years and 74 days, 60Co and 192Ir are not suitable candidates for this procedure. While 137Cs has also been used for breast irradiation, it too has an unaccept- ably long half-life for permanent implantation. The remaining two radionuclides now regularly used for brachytherapy are 125I and 103Pd. While clinical results using LDR 125I seeds have been reported for temporary implants in APBI (Vicini et al. 1997), clinical results have not been reported for permanent implants of 125I or 103Pd for APBI.

Recently, Keller et al. (2005) have reported on a feasibility study using both radionu- clides for APBI. CT data from ten patients with early-stage breast cancer were used to simulate 125I and 103Pd implants. Calculations of radiobiological equivalence were used to estimate a teletherapy dose of 50 Gy delivered over 25 fractions to the appropriate source strengths and total activities in the simulations. Doses of 90 Gy and 124 Gy were needed for 103Pd and 125I, respectively. Based on the photon energies and resultant dose fall-off, 103Pd was considered to be a suitable candidate for APBI permanent implants, while 125I was not recommended for APBI permanent implants due to radiation safety concerns. The results of Keller et al. were not strongly dependent on breast size or tumor bed volume across the ten patients simulated. Consequently, a phase I/II investigator- initiated clinical trial was started at the Sunnybrook and Women’s College Health Sci- ences Centre in 2004 using stranded 103Pd, with promising clinical results so far (Pignol et al. 2005). With a 103Pd implant, the dose rate would drop to one-fourth the initial dose rate after 1 month, and it is unclear if the 103Pd half-life is appropriately suited to the growth rate of breast carcinoma. Also, it is not clear if the stranded implant would unduly obscure follow-up mammograms. More clinical investigation of this novel ap- proach to APBI brachytherapy is required to fully access its potential role.

14.3.2 Microbrachytherapy

The new field of microbrachytherapy (μBx) takes the concept of brachytherapy to the domain of extremely small distances. While not classified as nuclear medicine, μBx employs tiny sealed sources of radionuclides, typically using 90Y, and is both calibrated and administered in a manner similar to nuclear medicine. 90Y μBx is currently used to treat non-resectable hepatic malignancies (Herba et al. 1988; Sarfaraz et al. 2003), and an in depth review of μBx is provided by Thomadsen et al. (2005). While animal stud- ies have been performed to determine the effects of a 90Y nuclear medicine agent on human breast cancer tumors (HBT 3477) implanted in athymic mice (DeNardo et al.

1998), there is no available literature at this time presenting the use of μBx in humans

or subsequent clinical results for breast cancer let alone APBI. Since the principles cur-

rently exploited for μBx primarily rely on microvascular electrostatics for radionuclide

localization primarily in the liver, new targeting systems will be needed to customize this

therapy modality for APBI.

14. New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation 

14.3.3 Electronic Brachytherapy

Since the discovery of 226Ra, radionuclide-based brachytherapy sources have been in clinical use for over 100 years. Currently, the large majority of brachytherapy implants use the following radionuclides: 103Pd, 125I, 137Cs, and 192Ir. While well-established, ra- dionuclides are limited due to:

1. Fixed dosimetric properties such as their radiation emission spectrum and tissue penetration.

Fig. 14.3

X-ray generation system for the Axx- ent electronic brachytherapy source by Xoft. Top-

positioned above the flexible source component.

Top-right The portable controller is positioned in

front of a test phantom with a flexible shield over the implanted region. Beneath the table is the cali- bration system (electrometer and reentrant well ionization chamber). Bottom The internal geom- etry of the source component is shown inside the cooling catheter

Fig. 14.4

Dose rates from the Axxent APBI system set to an operating voltage of 50 kV in comparison to conventional radionuclide-based brachytherapy sources. While the Axxent system has similar dose rates to HDR 192Ir at clinically relevant distances, the dose fall-off is similar to that of 125I

Fig. 14.5

The effect of running the Axxent elec-

tronic brachytherapy source at various operating

voltages, as well as the level of agreement between

ionization chamber measurements and Monte

Carlo calculations at each operating voltage over a

large range of distances

Mark J. Rivard, Alphonse G. Taghian and David E. Wazer

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2. Their source strength decays logarithmically requiring concerns for radiological waste storage and new source replacement.

3. National security and safety concerns by the U.S. Department of Homeland Security and U.S. Nuclear Regulatory Commission since 11 September 2001.

Thus, an alternative to radionuclide-based brachytherapy sources would be of interest.

With advances over the past few decades in the field of electrical miniaturization, it is now possible to create and use electronic brachytherapy (eBx) sources. Significant research over the past two decades has been performed to develop x-ray-emitting eBx sources. The interested reader is referred to a more detailed review article by Rivard et al. (2005) describing the current status of this field. While the Intrabeam IORT system from Carl Zeiss is the first and only eBx system currently having FDA approval, we will focus on the Axxent system by Xoft since this product is designed specifically to address the needs of APBI.

The company Xoft, initially incorporated to provide eBx sources for intravascular brachytherapy and treating coronary artery disease, focused in 2001 on developing eBx sources for APBI (Rusch and Rivard 2004). Similar to the Intrabeam system, a miniature x-ray tube operating at 50 kVp and 300 μA is available (Fig. 14.3) with a source strength similar to HDR 192Ir, yet with dosimetric properties and shielding requirements similar to LDR 125I. Xoft will sponsor a multicenter phase IV trial to assess safety and utility of their Axxent APBI system manner similar to that previously initiated by Proxima Thera- peutics for the MammoSite system. Having their own assortment of balloon applica- tors, ten treatment fractions are to be delivered twice daily over 5 days with an radiation dose of 3.4 Gy at a distance of 10 mm from the balloon transverse plane, identical to the MammoSite approach. Figure 14.4 illustrates the potential dose rates of the Axxent APBI system at clinically relevant depths in comparison to HDR 192Ir and LDR 125I and 103Pd brachytherapy sources. Compared to HDR 192Ir, there is a slight increase in dose rate at radii closer than 3.0 cm with lower dose rates at larger distances. Figure 14.5 shows the effect of running the Axxent eBx source at various operating voltages, as well as the level of agreement between ionization chamber measurements and Monte Carlo calculations at each operating voltage over a large range of distances. At distances of 3 cm and 7 cm, going from 40 to 50 kV increases relative penetration by 20% and a factor of two, respec- tively. As the time of writing, FDA clearance for the Axxent is approved.

14.4 Summary

A variety of potential and novel modalities have been presented as treatment delivery

techniques for APBI. Some of these approaches have already been used clinically, while

others are still being developed at the benchtop. Just as conventional APBI techniques

have advanced over the past decade to include interstitial HDR 192Ir needles and the

MammoSite system, it is anticipated that some of these new and novel treatment deliv-

ery techniques may eventually have a role for administering APBI.

14. New and Novel Treatment Delivery Techniques for Accelerated Partial Breast Irradiation 

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