Adaptive radiation therapy of breast cancer by repeated imaging during irradiation.

Breast cancer is the most frequent cancer among females and also a leading cause of cancer related mortality worldwide. A multimodality treatment approach may be utilized for optimal management of patients with combinations of surgery, radiation therapy (RT) and systemic treatment. RT composes an integral part of breast conserving treatment, and is typically used after breast conserving surgery to improve local control. Recent years have witnessed significant improvements in the discipline of radiation oncology which allow for more focused and precise treatment delivery. Adaptive radiation therapy (ART) is among the most important RT techniques which may be utilized for redesigning of treatment plans to account for dynamic changes in tumor size and anatomy during the course of irradiation. In the context of breast cancer, ART may serve as an excellent tool for patients receiving breast irradiation followed by a sequential boost to the tumor bed. Primary benefits of ART include more precise boost localization and potential for improved normal tissue sparing with adapted boost target volumes particularly in the setting of seroma reduction during the course of irradiation. Herein, we provide a concise review of ART for breast cancer in light of the literature. ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: Adaptive radiation therapy (ART) refers to redesigning of treatment plans with respect to dynamic changes in tumor size and anatomy during the course of irradiation. There have been several applications of ART for a variety of cancers. In the context of breast cancer, ART may serve as an excellent tool for patients receiving breast irradiation followed by a sequential boost to the tumor bed. Primary benefits of ART include more precise boost localization and potential for improved normal tissue sparing with adapted boost target volumes particularly in the setting of seroma reduction during the course of irradiation.

INTRODUCTION

Breast cancer is the most frequent cancer among females and also a leading cause of cancer related mortality worldwide. A multimodality treatment approach may be utilized for optimal management of patients with combinations of surgery, radiation therapy (RT) and systemic treatment. RT composes an integral part of breast conserving treatment (BCT), and is typically used after breast conserving surgery (BCS) to improve local control. Recent years have witnessed significant improvements in the discipline of radiation oncology which allow for more focused and precise treatment delivery. Adaptive radiation therapy (ART) is among the most important RT techniques which may be utilized for redesigning of treatment plans to account for dynamic changes in tumor size and anatomy during the course of irradiation. In the context of breast cancer, ART may serve as an excellent tool for patients receiving breast irradiation followed by a sequential boost to the tumor bed. Primary benefits of ART include more precise boost localization and potential for improved normal tissue sparing with adapted boost target volumes particularly in the setting of seroma reduction during the course of irradiation. Herein, we provide a concise review of ART for breast cancer in light of the literature.

MASTECTOMY AND BREAST CONSERVING TREATMENT FOR BREAST CANCER MANAGEMENT

Both mastectomy and BCT are widely used therapeutic options for management of patients suffering from breast cancer. Selection of surgical modality as BCS or mastectomy is based on several factors including patient and tumor characteristics, assessment of outcomes in terms of cosmesis, treatment morbidity and local control, and patient preferences. In terms of efficacy, BCT and mastectomy provide comparable results which have been supported by data from randomized trials and collaborative group studies[1-3]. In this context, BCT has been alternatively used for management of patients with breast cancer. Recent studies also support the utility of BCS and RT as a viable alternative to mastectomy with encouraging results[4-8].

UTILITY OF RADIATION THERAPY AS PART OF BREAST CONSERVING TREATMENT

Use of RT as part of BCT is increasing in line with accumulating evidence and improvements in the discipline of radiation oncology including sophisticated delivery techniques and modernized treatment equipment[9,10]. Although omission of RT after BCS may be considered for a very highly selected subgroup of patients given the relatively lower local recurrence rates after BCS and endocrine treatment[11-13], RT is widely recognized as an integral part of BCT particularly to decrease the rates of local recurrence[14-21].

CONVENTIONALLY FRACTIONATED RADIATION THERAPY OF THE INTACT BREAST: TO BOOST OR NOT TO BOOST

Irradiation of the intact breast with conventionally fractionated RT as part of BCT typically includes whole breast irradiation (WBI) followed by a sequential tumor bed boost directed at the lumpectomy cavity. Main rationale of adjuvant RT following BCS is reduction of local recurrence. Utility of RT for breast cancer management has been assessed in a comprehensive metaanalysis[14]. This metaanalysis reported a substantial reduction in the 10-year first recurrence rate from 35% to 19.3%, and incorporation of adjuvant RT also resulted in a breast cancer survival gain of 3.8% at 15 years, suggesting substantial benefit of adding RT after surgical management[14]. Since local recurrence comprises a critical pattern of recurrence for breast cancer patients affecting prognosis[22,23], achieving durable local control rates is a pertinent goal of management. Given the tendency of breast tumors to recur primarily at the original tumor site, delivery of a boost RT dose to the lumpectomy cavity has been utilized for achieving improved local control rates[24-33]. Rationale for boost RT includes elimination of microscopic tumor cells located at the primary tumor site to improve local control. Delivery of boost dose to the lumpectomy cavity may be performed by use of several techniques including external photon beams, external electron beams, and brachytherapy[24,25,34].

DEFINITION OF THE BOOST TARGET VOLUME

Definition of the boost target volume is a critical component of breast cancer RT. Surgical scar and clips, ultrasonography, mammography, Computerized Tomography (CT), Magnetic Resonance Imaging (MRI), clinical examination findings may be incorporated for determining the localization of tumor bed boost[35-44]. However, there is no consensus on this critical issue with wide variations among clinical practices worldwide. Clearly, all methods have their advantages and drawbacks which renders a complementary or integrative approach more feasible to achieve precise target volume localization.

THE CONCEPT OF ADAPTIVE RADIATION THERAPY

ART refers to redesigning of treatment plans with respect to dynamic changes in tumor size and anatomy during the course of irradiation. There have been several applications of ART for a variety of indications including breast cancer, head and neck cancers, prostate cancer, and several other cancers throughout the human body[45-52]. Primary objective of ART is achieving an improved therapeutic ratio. Accounting for volumetric and anatomical changes during the course of irradiation has great potential for improving treatment outcomes. This pertinent goal of RT may be achieved by incorporating smaller boost target volumes when substantial reduction in tumor burden is confirmed on periodical imaging during the RT course. Indeed, this rationale has been tested in the setting of RT after induction chemotherapy for limited-stage small cell lung cancer[53]. The authors concluded that irradiation of the postchemotherapy volumes instead of baseline prechemotherapy volumes did not decrease locoregional control[53]. While chemotherapy may confer substantial shrinkage of tumor volumes particularly for chemosensitive cancers, RT may also achieve reduction in tumor burden which may be exploited by use of ART techniques. Besides tumor shrinkage, replanning for boost RT may provide additional advantages for precise target localization accounting for the potential changes in patient anatomy due to weight loss or edema.

ADAPTIVE RADIATION THERAPY OF THE INTACT BREAST BY REPEATED IMAGING DURING THE COURSE OF IRRADIATION

For breast cancer patients receiving conventionally fractionated RT over 5-6 wk followed by a sequential tumor bed boost, ART may be utilized for more precisely focused boost RT. Replanning for the tumor bed boost may prevent excessive normal tissue exposure particularly for patients having seroma at the initiation of WBI. Several studies have reported on volumetric changes in the lumpectomy cavity during te course of breast irradiation[45,54-63]. Data from selected studies incorporating ART for breast cancer by use of repeated imaging during the course of breast irradiation are summarized in Table 1.

Table 1

Selected studies incorporating adaptive radiation therapy for breast cancer by use of repeated imaging during the course of breast irradiation

Ref.	Year of publication	Number of patients receiving ART by use of repeated imaging	Relevant findings at initial imaging for RT	Relevant findings at repeated imaging for boost RT	P value
Oh et al[55]	2006	30	Cavity volume before WBI 32.1 cc	Cavity volume after WBI 25.1 cc	< 0.0001
Sharma et al[56]	2009	24	Median seroma volume 50 cc before WBI	Median seroma volume 29 cc at repeated CT-simulation for tumor bed boost	< 0.001
Tersteeg et al[57]	2009	77	Gross Tumor Volume before WBI 78.7 cc	Gross Tumor Volume 29.7 cc at repeated CT-simulation for tumor bed boost	< 0.001
Flannery et al[58]	2009	43	Median lumpectomy volume 38.2 cc at initial CT-simulation for WBI	Median lumpectomy volume 21.7 cc at repeated CT-simulation for tumor bed boost	< 0.001
Hurkmans et al[59]	2009	10	Boost volume 40 cc at initial CT-simulation for WBI	Boost volume 25-28 cc at repeated CT-simulations for tumor bed boost	= 0.02
Alderliesten et al[60]	2011	21	Mean seroma volume 63 cc at initial CT-simulation for WBI	Mean seroma volume 25 cc at repeated CT-simulation for tumor bed boost	< 0.001
Cho et al[61]	2011	70	Lumpectomy cavity volume 50.4 cc before WBI	Lumpectomy cavity volume 40.7 cc after WBI	< 0.001
Hurkmans et al[62]	2012	113	Tumor bed volume 70 cc at initial CT-simulation for breast RT	Tumor bed volume 45 cc at repeated CT-simulation	< 0.001
Mohiuddin et al[63]	2012	40	Median lumpectomy cavity volume 42 cc at initial CT-simulation for WBI	Median lumpectomy cavity volume 22 cc at repeated CT-simulation for tumor bed boost	< 0.001
Sager et al[45]	2018	48	Median boost target volume 33.85 cc at initial CT-simulation for WBI	Median boost target volume 14.55 cc at repeated CT-simulation for tumor bed boost	< 0.0001

ART: Adaptive radiation therapy; RT: Radiation therapy; CT: Computed tomography; WBI: Whole breast irradiation.

A consistent finding of the aforementioned studies is the dynamic nature of the tumor bed during the course of breast irradiation. In this context, ART may be exploited to optimize normal tissue sparing particularly in the presence of substantial seroma reduction during RT by using reduced boost target volumes. Another potential benefit of repeated imaging may be avoidance of boost localization inaccuracies due to dynamic changes during the course of breast irradiation which may allow for improved precision in boost RT. These potential benefits of ART should be considered thoroughly for management of patients with breast cancer to achieve an improved therapeutic ratio. Figure 1 shows axial CT images of a patient acquired at initial CT-simulation (on the left) for WBI planning and repeated CT-simulation (on the right) for tumor bed boost planning.

Figure 1

Axial computed tomography images. A patient acquired at initial computed tomography-simulation (on the left) for whole breast irradiation planning and repeated computed tomography-simulation (on the right) for tumor bed boost planning.

CONCLUSION

ART with repeated imaging during the course of irradiation may serve as an excellent tool for patients receiving breast RT followed by a sequential boost to the tumor bed. Utility of ART with widely accepted hypofractionated breast irradiation protocols, frequency of imaging for treatment plan adaptation, selection of patients for ART or routinization of the technique for every patient are areas of active investigation. There is accumulating evidence supporting the utility of ART for breast cancer management, however, future trials are needed for validation of dosimetric and clinical results of ART with repeated imaging at different time points during the course of breast irradiation.