Advancements in brachytherapy

ADR-13059; No of Pages 12 Advanced Drug Delivery Reviews xxx (2016) xxx–xxx

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Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

Advancements in brachytherapy☆

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Kari Tanderup a,⁎, Cynthia Menard b, Csaba Polgar c, Jacob Lindegaard a, Christian Kirisits d, Richard Pötter d

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Article history: Received 23 January 2016 Received in revised form 14 June 2016 Accepted 5 September 2016 Available online xxxx

Department of Oncology, Aarhus University Hospital, Aarhus, Denmark Centre Hospitalier de l'Université de Montréal, Montréal, Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada c Center of Radiotherapy, National Institute of Oncology, Budapest, Hungary d Department of Radiotherapy, General Hospital of Vienna, Vienna, Austria

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Brachytherapy is a radiotherapy modality associated with a highly focal dose distribution. Brachytherapy treats the cancer tissue from the inside, and the radiation does not travel through healthy tissue to reach the target as with external beam radiotherapy techniques. The nature of brachytherapy makes it attractive for boosting limited size target volumes to very high doses while sparing normal tissues. Significant developments over the last decades have increased the use of 3D image guided procedures with the utilization of CT, MRI, US and PET. This has taken brachytherapy to a new level in terms of controlling dose and demonstrating excellent clinical outcome. Interests in focal, hypofractionated and adaptive treatments are increasing, and brachytherapy has significant potential to develop further in these directions with current and new treatment indications. © 2016 Elsevier B.V. All rights reserved.

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Keywords: Brachytherapy Radiotherapy Image guided therapy Hypofractionation Focal therapy Technology Imaging

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Contents

Overview of brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Physical and radiobiological effects . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Clinical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3. Dose and volume effects for target, OARs and specific morbidity endpoints in brachytherapy 1.4. Advantages of brachytherapy over EBRT . . . . . . . . . . . . . . . . . . . . . . . . 2. Advancements in planning and delivery technology — conventional and novel techniques . . . . . 2.1. Conventional techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Novel concepts and techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Risk and response adaptive target definition . . . . . . . . . . . . . . . . . . 2.2.2. Image modalities for adaptive and individualized brachytherapy . . . . . . . . . 2.2.3. Real-time imaging for implantation . . . . . . . . . . . . . . . . . . . . . . 2.2.4. Developments of applicators . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.5. Image based treatment planning . . . . . . . . . . . . . . . . . . . . . . . 2.2.6. Developments within treatment delivery verification . . . . . . . . . . . . . . 3. Future outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Radiotherapy for Cancer: Present and Future”. ⁎ Corresponding author. E-mail address: [email protected] (K. Tanderup).

http://dx.doi.org/10.1016/j.addr.2016.09.002 0169-409X/© 2016 Elsevier B.V. All rights reserved.

Please cite this article as: K. Tanderup, et al., Advancements in brachytherapy, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/10.1016/ j.addr.2016.09.002

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1. Overview of brachytherapy

1.2. Clinical applications

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1.1. Physical and radiobiological effects

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Brachytherapy, also known as internal radiotherapy, is the delivery of radiotherapy with the use of sealed radioactive sources. Brachytherapy can be applied as mono-therapy or in combination with external beam radiotherapy (EBRT), surgery, and/or chemotherapy. Brachytherapy requires implantation of catheters and advances the radioactive source(s) into the patient through intracavitary, intraluminal or interstitial (needles) applicators. Brachytherapy sources can be permanently implanted or the delivery can be temporary with remote afterloading where a mobile source is advanced from a sealed safe, into the catheters, and retracted back into the safe after the treatment is delivered. Brachytherapy is characterized by a steep dose fall off with increasing distance to the radioactive source. The dose fall off is approximately proportional to 1/r2, where r is the distance to the source [1]. Typical dose gradients at the border of a target are as high as 5–20% per mm. The pronounced dose gradients result in a highly heterogeneous 3D dose distribution, and the median target dose is typically higher than 150–200% of the prescribed dose (Fig. 1) [2]. Geometric deviations in the order of mm's may have considerable impact on a given dose distribution due to the steep brachytherapy gradients [3,4]. Whereas margins are routinely used in EBRT to compensate for uncertainties, this is only partly possible in brachytherapy [5]. The catheter implantation defines the volume which can be reached with a relevant dose, and therefore the quality of the implantation is of specific importance in brachytherapy. Dose optimization in afterloading brachytherapy can adjust dose deposition only by around 1–5 mm, as more extensive optimization may result in unacceptable high dose regions around the brachytherapy applicators and in adjacent organs at risk. If the catheters are unfavorably positioned it is therefore not possible to reach an optimal dose. Afterloading high dose rate (HDR) brachytherapy is hypofractionated and typically delivered in 1–10 fractions of 3–20 Gy depending on the indication. The combination of high central dose and hypofractionation leads to a significant enhancement of the biological effect leading to an ablative effect in the high dose regions. Due to the physical characteristics and the biological effects it is possible to routinely deliver more than e.g. 80–90 Gy biologically equivalent dose in 2-Gy fractions (EQD2) to the tumor periphery while the central tumor target receives even higher doses (e.g. N 120 Gy EQD2) [6,7] (Fig. 1). The ability to deliver such a high dose to central disease explains the excellent local control rates achieved with brachytherapy e.g. in cervix, prostate and breast cancer.

The precondition for clinical applications for brachytherapy in the past 100 years has been direct clinical tumor access and limited size tumor volume (up to 50–100 cm3). The most common sites for administration of brachytherapy nowadays are gynecologic and prostate cancer. Furthermore, brachytherapy is used for breast, skin, anus and rectum, sarcoma, head and neck, bladder, lung, esophagus, bile duct, liver and ocular malignancies. Among gynecologic brachytherapy applications, cervix cancer is the most common site, and the vast majority of all brachytherapy procedures worldwide are in locally advanced cervix cancer [8] treated definitely with a combination of external beam radiochemotherapy and brachytherapy. EBRT covers the elective lymph node target as well as the primary tumor to 45–50 Gy, and may be used to boost pathologic lymph nodes. Brachytherapy is normally delivered towards the end of EBRT to boost the residual target to doses larger than 65 and 100 Gy. Other gynecologic brachytherapy applications include adjuvant vaginal irradiation after surgery in endometrial cancer [9],definitive treatment of primary vaginal and endometrium cancer as well as recurrences. Prostate radiotherapy can be administered by several radiotherapy modalities including EBRT, brachytherapy, proton radiotherapy or as a combination of EBRT and brachytherapy. Broad experience is available in all fields, but controversy remains within the field on the optimal modality for radiation delivery. There is level 1 evidence that dose matters, whereby dose-escalation results in improved cancer outcomes. Although this has been demonstrated with modest dose escalation using external beam approaches [10], it has also been demonstrated with the use of a brachytherapy boost in patients with intermediate and high-risk disease where a more dramatic dose escalation can be safely achieved with equitoxic outcomes [11]. For patients with lowerrisk disease, outcomes are excellent regardless of the therapeutic approach, and much of the controversy revolves on the appropriate selection of patients for a therapeutic intervention versus active surveillance. In this regard, brachytherapy monotherapy has been a predominant approach given its convenience, cost-effectiveness, and favorable side-effect profile. Interstitial breast brachytherapy with rigid needles or multiple flexible catheters can be used to boost the tumor bed after breastconserving surgery and whole-breast EBRT. Re-excision followed by re-irradiation using interstitial BT has also been used as an alternative to mastectomy to treat ipsilateral breast local recurrence after previous breast conserving therapy. In the last two decades, the new concept of accelerated partial breast irradiation (APBI) limiting radiation to the vicinity of the surgical cavity opened a new perspective for breast

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Fig. 1. Dose profiles for external beam radiotherapy (EBRT) (dashed) and brachytherapy (full) across the pelvis for a typical cervix cancer case. The colors indicate target regions at different risk of disease failure: elective lymph node target (blue), intermediate risk target volume (light red) and high risk target volume (red). The left panel shows relative physical doses. The right panel shows total EBRT and brachytherapy dose which has been recalculated into biological equivalent dose in 2Gy fractions (EQD2) in a combined EBRT + BT treatment of cervix cancer. Red dashed lines in the right panel indicate dose levels which are currently regarded as appropriate for control of microscopic lymph node disease (45 Gy) and residual pathological tissue at time of brachytherapy (85 Gy) in cervix cancer. Adapted from ICRU report 89[2]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Please cite this article as: K. Tanderup, et al., Advancements in brachytherapy, Adv. Drug Deliv. Rev. (2016), http://dx.doi.org/10.1016/ j.addr.2016.09.002

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Local and regional tumor control as well as acute and late morbidity in radiotherapy are correlated with prescribed dose as well as with the entire 3D dose distribution. A range of statistical models can predict clinical outcome from radiotherapy dose and volume parameters in combination with clinical and other treatment related factors. The consequence of a certain dose distribution is related to normal tissue subunits and overall organization. Classically, tissues have been characterized as serial or parallel structures or as combinations of these [15]. In serial structures, all subunits need to be functional, and typical examples are rectum, bowel, and sphincters. In parallel structures the function is determined by the total amount of available functional subunits with typical examples being lung and liver. An organ structure may include different biological targets, e.g. small vessels, mucosa, fibroblasts related to different symptoms such as bleeding, functional impairment due to mucosal function, and fibrosis/ induration. On the other hand, a specific symptom may be associated with several underlying mechanisms with additive impact, e.g. both the anal sphincter and the reservoir function of the rectum may have impact on fecal incontinence. When evaluating dose–effect relationships the total radiobiological equi-effective dose must be taken into account [2]. Brachytherapy is often combined with EBRT and the total dose distribution involves the characteristic focal dose (e.g. N85 Gy EQD2) in proximity to the brachytherapy implant as well as larger organ volumes irradiated to low and intermediate dose levels of e.g. 20–50 Gy (Fig. 1). Typical examples of morbidity endpoints related to small volumes irradiated to high doses are ulcerations, radionecrosis, fistula and bleeding, fibrosis such as vaginal stenosis, and partly functional irritation such as urinary urgency and frequency [16–19]. Larger volumes irradiated to less high and intermediate doses with more contribution from EBRT may drive other endpoints such as diarrhea, bowel strictures, bladder shrinkage and also functional impairments such as anorectal urgency and incontinence. Fig. 2 shows examples of vaginal morbidity: ulcerations are typically related to the high brachytherapy doses, while milder overall changes such as atrophy and telangiectasia may be related to intermediate dose levels. Furthermore, the specific combinations of brachytherapy with surgery, chemotherapy, hormonal therapy and targeted agents, also impacts morbidity patterns related to the interaction of the different treatment modalities [20]. Knowledge of radiotherapy dose and volume effects as well as understanding of underlying mechanisms are the keys to direct brachytherapy practice into the most promising directions for improvement of local control, reduction of toxicity and improvements in Quality of Life. The introduction of 3D image guided brachytherapy facilitated

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Fig. 2. Vaginoscopy performed in cervix cancer patient before and after definitive radiochemotherapy and brachytherapy. A) Appearance of normal vagina before radiotherapy. B) Mild atrophy and mild mottle pale color. C) A scar at 10 o'clock, telangiectasia, confluent erythema, and areas with pallor. D) Ulceration and telangiectasia. Courtesy Kathrin Kirchheiner, Medical University of Vienna.

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improved contouring and reporting [21–24], and has significantly im- 209 proved the possibilities to identify dose effect relationships [25–27]. 210

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interstitial brachytherapy. APBI using multi-catheter BT implants has been evaluated in phase I–II and phase III clinical trials as a possible alternative to conventional whole-breast EBRT [12,13]. Beyond classical multicatheter interstitial brachytherapy, intracavitary single-entry breast BT applicators have been developed to decrease the number of catheters to be implanted while easing the implantation procedure [14]. For the other clinical applications as mentioned in the first paragraph of Section 1.2, a variety of clinical scenarios exist and techniques of brachytherapy which are beyond the scope of this review. The general rule for any brachytherapy scenarios and techniques including is that high focused doses can be achieved in limited size volumes within a short overall treatment time. This leads to excellent local effects with only few severe side effects. What will be elaborated in the following paragraphs of this review, in general and specified for gynecology, prostate and breast, therefore also applies for the other traditional and future fields of brachytherapy, with modifications as appropriate.

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1.4. Advantages of brachytherapy over EBRT

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The physical properties of photon EBRT, protons and brachytherapy are entirely different. Protons have a finite range due to the dense interaction between charged particles and tissue, which facilitates sparing of tissue “behind” the target. Photons from both EBRT and brachytherapy interact less intensively with tissue than protons and the effect of absorption is much less pronounced for these two modalities. The most significant difference between EBRT and brachytherapy is the proximity of the radiation source to the target which has huge impact on the dose to the central part of the tumor. Brachytherapy treats the cancer from the inside. The radiation does not travel through healthy tissue to reach the target, and it is normally possible to reach significantly higher target doses and better sparing of normal tissues than with protons and EBRT [28–30]. It is possible to deliver brachytherapy in fewer fractions than with EBRT. For patients, shorter treatment time is an advantage, and furthermore hypofractionation may also be exploited radiobiologically. On top of the advantageous physical properties, brachytherapy applications have favorable direct clinical guidance. EBRT treatment planning is almost exclusively based on 3D image based target definition which may be suitable for visualization of gross tumor volumes, while identification of superficial mucosal invasion or positive margins after surgery is not possible. Brachytherapy applications are steered by clinical examination (e.g. palpation) and visual inspection as e.g. in gynecology where the positioning of an applicator is guided by the appearance and palpation of the tumor infiltration as well as of the visual and digital examination of the vagina. Bronchoscopy, esophagoscopy, cystoscopy, rectoscopy and laparoscopy are examples of visual assessment used for direct guiding of the applicator positioning. Furthermore, brachytherapy has some advantages over EBRT related to the needs for EBRT to expand the irradiated volume by uncertainty margins in order to secure target coverage [31].The brachytherapy irradiation device, is placed inside or in direct proximity to the tumor and will therefore follow any tumor movement or at least to a large degree

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Novel techniques in brachytherapy have exploited imaging and novel target concepts as well as technology developments of brachytherapy applicators and software allowing for individualized image guided applications and advanced treatment planning (Fig. 3).

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2.2.1. Risk and response adaptive target definition

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2.2.1.1. General GTV and CTV concepts. The gross tumor volume (GTV) and the clinical target volume (CTV) are general oncological concepts [31]. GTV identifies the gross tumor volume as it appears according to clinical examination and/or on imaging such as CT, US, PET or MRI. The CTV includes the GTV as well as assumed subclinical disease requiring treatment. Regions at risk of subclinical disease may be identified along typical pathways of tumor cell spread such as adjacent anatomical compartments and lymphatic pathways. In cases where the entire GTV is removed by surgery (e.g. in breast cancer), there will only be a CTV.

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2.2.1.2. Risk adapted target volume selection. Whereas surgery is a “dichotomized” approach where the targeted tissue is either removed or not, radiotherapy tunes the intensity of treatment to the burden of disease. Larger tumor size is in general treated with higher radiation dose. Furthermore, within a given target, there may be varying density of cancer stem cells and varying radioresistance [53–55]. The discrimination between different GTVs and CTVs facilitates risk tailored dose application, and brachytherapy can play a specific role in advancing focused dose escalation according to tumor characteristics [56,57]. Furthermore, there has been growing interest in describing the pattern of tumor spread at diagnosis and the pattern of recurrences using advanced forms of imaging. Such knowledge also supports the utilization of risk adapted target volumes.

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Classical brachytherapy has been focused on an optimal arrangement of sources with the aim of creating dose distributions with balanced heterogeneity. The treatment principles were founded more than half a century ago in leading centers forming the traditional clinical schools such as e.g. the Paris School [49]. These schools varied significantly in treatment techniques, applicators, treatment planning, prescription of radiation dose and fractionation. The communication between the various schools was hampered by lack of a common language. There have been barriers for sharing and comparing dose and fractionation, techniques and clinical outcome, and this has been a major obstacle for the development and implementation of new brachytherapy techniques. Administration of classical brachytherapy was based on clinical examination and 2D X-ray imaging. Significant advances in EBRT took place in the 1990s with the systematic introduction of CT based treatment planning which allowed for individualized target definition and OAR contouring based on volumetric imaging, 3D image based dose prescription and treatment planning with arrangement of radiation fields to conform the dose distribution to the target region. In cervix and breast cancer brachytherapy no parallel 3D imaging developments were seen at that time. In prostate cancer, ultrasound (US) was introduced as early as the 1980s [50] and allowed to perform implantation of radioactive seeds guided by sectional US imaging and US based treatment planning [51]. For cervix and other sites for brachytherapy it was not until the 90s that the first pilot experience indicated that 3D imaging has significant potential [52].

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joint recommendations for 3D image based target definition, dose 310 reporting as well as developments of novel applicator designs [21–24, 311 43]. 312

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[5]. Both inter- and intra-fraction motion in EBRT applications are considerable challenges although significant progress has been obtained within on-board (3D) imaging and new developments in intra-fraction motion management [32,33]. Due to new EBRT technologies such as IMRT, SBRT and heavy particle radiotherapy there are continuous considerations whether brachytherapy could be replaced by EBRT. There are trends of diminished use of brachytherapy in cervix cancer [34,35] and prostate cancer [36,37]. The reasons for this are not completely clear [38,39], but may be related to lack of expertise, to re-imbursement issues favoring EBRT, or to growing attitudes favoring avoidance of any invasive procedures. However, there are clear indications that e.g. cervix cancer patients treated with combined EBRT and brachytherapy have significantly better overall survival than patients treated with EBRT only [34,35]. This improved outcome is as expected from the physics of brachytherapy which enables delivery of significantly higher doses to the target, than the most advanced IMRT, SBRT or proton techniques [29]. Prostate brachytherapy, either as monotherapy or as a boost to external beam radiotherapy, can achieve unparalleled dose escalation, with EQD2 upwards of 150 Gy [7]. Compared with modern external beam series (EQD2 ~ 78Gy), brachytherapy results in improved cancer outcomes and reduced rectal toxicity at the cost of urinary function [40–42]. Brachytherapy involves a minimal level of invasiveness and anesthesia, which carries risk of acute bleeding, infection, and cardiopulmonary events. In an elderly patient demographic with comorbidities and frequent underlying obstructive urinary function from benign prostatic hyperplasia, these limitations cannot be dismissed. In general, younger fit patients with good baseline urinary function are selected for a brachytherapy approach to dose escalation [24,43]. The standard technique of RT after breast conserving surgery is to treat the whole breast by EBRT up to a total dose of 45–50 Gy. An additional boost dose of 10–16 Gy to the tumor bed further reduces the local recurrence rate and can be delivered with either EBRT or interstitial brachytherapy [44]. Interstitial brachytherapy offers the practical advantage of more conformal treatment of small volumes to higher doses and lower doses to the skin [45]. Therefore, interstitial brachytherapy is preferable in cases of deep-seated tumor bed in large volume breasts. APBI is a treatment approach that shortens the 5- to 7-week course of postoperative EBRT to 4–5 days while limiting irradiation to the vicinity of the lumpectomy cavity. Using permanent seed implants the treatment procedure can be further shortened to a 1 h procedure [46]. The acceleration of RT eliminates some disadvantages of the extended treatment period, especially for elderly patients, working women and those who live at a significant distance from the RT facility. By avoiding irradiation of the whole breast, the dose to the normal tissues (e.g. healthy breast parencyhma, skin, lungs and heart) can be dramatically decreased [28]. The first technique utilized in early APBI studies was multicatheter interstitial brachytherapy [47]. The implementation of other techniques (including 3D conformal EBRT and intraoperative RT) to deliver APBI was based on the success of these phase I-II clinical studies using multicatheter breast implants. However to date, only multicatheter interstitial brachytherapy proved to be non-inferior to whole-breast EBRT in prospective randomized clinical trials while also demonstrating improved cosmetic outcome [13].

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2. Advancements in planning and delivery technology — conventional and novel techniques The integration of advanced volumetric (3D) imaging in brachytherapy has been a major progress in brachytherapy during the last decades. With focal irradiation, it has been logical to invest in improved precision of target definition and identification of organs at risk, as this defines the success to cover the disease appropriately and avoid high exposure of organs at risk. Investments in multimodality imaging and imaging with applicator in place, has played a major role [48] supported by

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Fig. 3. Example of an advanced workflow of adaptive image guided brachytherapy in cervix cancer. A) Pre-planning of fractionation schedule and implant geometry with adaptation to tumor response during EBRT. B) Applicator insertion/implantation with online ultrasound guidance. C) MR imaging and target identification. D) OAR definition as well as applicator reconstruction. E) Dwell time optimization and dose and volume assessment. F) Dose delivery with in-vivo dosimetry verification.

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In prostate brachytherapy the developments within multiparametric MRI have significantly improved the ability to identify primary lesions within the prostate [58]. The conventional approach in prostate cancer radiotherapy has been to irradiate the entire prostate gland to a specific dose level, with dose specification at the periphery of the clinical target volume covering the whole gland. Another dose specification has been proposed within the prostate, e.g. for the peripheral zone, harboring usually the major burden of prostate cancer [59]. However, with better quality of imaging, there is a growing interest in investigating risk adaptive strategies, where higher doses are delivered to the specific primary lesions within the gland compared to the rest of the gland with non-visible disease [60,61]. Furthermore, focal salvage

therapy relies on imaging and identification of a tumor sub-volume (Fig. 4). In breast brachytherapy a shift from radiography-based implant oriented dose prescription towards 3D CT image-based target definition and treatment planning occurred during the last two decades [62,63]. The application of CT for pre-implant and implant imaging has improved target volume coverage, dose homogeneity, and conformality [64]. Target definition for permanent seed breast implants relies on a combination of a CT-defined seroma for planning and US-defined seroma for real time implant guidance [46]. Recently, recommendations on target definition and delineation have been developed by GECESTRO in order to decrease inter-observer variability in target

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2.2.1.3. Tumor response and adaptive target volume selection. Response during cancer treatment induces changes in tumor volume and configuration which appears in various forms of GTV regression reflecting the biological radio-chemosensitivity. Response adaptive radiotherapy takes into account these changes by adapting the treatment strategy to the individual tumor response. Adaptive target volumes are identified during radiotherapy and additional radiation dose (boost) is prescribed to the residual limited size target volumes and not to the

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initial target volume which may be significantly larger. The individual treatment response is assessed clinically and with repeated imaging during radiotherapy. This approach has been pioneered during the last decade for the definitive treatment of cervical cancer with a potential of applying very high radiation doses to such adaptive high risk CTV (e.g. N85–90 Gy), to the residual GTV (e.g. N 100 Gy) and to the region of the initial GTV (intermediate risk CTV, 60–70 Gy). The clinical results show outstanding tumor control rates up to 100% in limited size tumors and 85–90% in large tumors [66,67]. The ICRU report 89[2] has for the first time systematically introduced into the international radiation oncology community the concept of an adaptive CTV which is based on the individual tumor response. There are more clinical tumor sites as candidates for such adaptive approach. Among these are rectal cancer, anal cancer and head and neck cancer. All these tumors are primarily treated by definitive radiochemotherapy and are often boosted with an additional radiation dose. Image guided adaptive brachytherapy has considerable potential in these tumor sites, which needs to be systematically explored in future

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delineation and to achieve consistent and reproducible image-based breast BT treatments [23,65]. According to the GEC-ESTRO recommendations a detailed knowledge of primary surgical procedure, of pathology report, as well as of preoperative imaging, and definition of tumor localization before breast conserving surgery inside the breast and translation of this information to the postoperative CT imaging dataset are needed for target delineation [23] (Fig. 5). Having the tumor bed identified and contoured, it should be expanded by up to 20 mm as an overall safety margin around the original tumor.

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Fig. 4. Case example of focal HDR brachytherapy boost to GTV visualized on T2w (top left) and DWI (ADC map top right) as an area of hypointensity and restricted diffusion in the right lateral peripheral zone. MRI-based dose plan in axial (bottom left) and sagittal (bottom right) planes (dashed purple = prostate, brown = rectum, yellow = bladder, red dots = dwell positions, solid isodose lines white = 150%, red = 125%, orange = 100%, purple = 75%, blue = 50%). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 5. APBI target definition on pre-implant CT (A) and dose distribution on post-implant CT (B).(A) Yellow line = excision cavity covering all titanium surgical clips (blue crosses); green line = expansion of the excision cavity with adequate margins; red line = final PTV excluding pectoral muscle and a 5 mm rim below the skin surface. (B) Thick red line = PTV; thin red line = reference (100%) isodose line covering N90% of the PTV ; light-blue line = 150% isodose line; yellow line = 75% isodose line; green line = 50% isodose line. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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2.2.3. Real-time imaging for implantation With real-time imaging it is possible to steer the catheters into place with a high accuracy and safety for the patient. Real-time imaging can in principle be performed with conventional radiography (fluoroscopy), US, MRI, CT and optical imaging (endoscopy). Optimally, the image modality used for real-time guidance is also suitable for discrimination of the tumor and the target volume as well as for the visualization of OARs. Therefore, fluoroscopic X-ray based real time imaging is not much used any more, but is rather being replaced by volumetric and endoscopic imaging. Prostate brachytherapy is the outstanding technical and clinical example for the successful integration of real-time imaging into the workflow of interstitial application. With real-time US imaging the needle implantation can be performed while visualizing the prostate gland as well as urethra and rectum. During the last decade new software optimization tools have been developed for prostate brachytherapy which can predict the most favorable catheter configuration based on the anatomy of the individual patient. Finally, US based treatment planning can be done while the patient is under anesthesia, and if the operating theater is shielded, treatment delivery can be performed directly afterwards to limit the impact of patient and catheter movement. Real-time TRUS guided brachytherapy has been introduced for interstitial and intracavitary brachytherapy in vaginal cancer and in vaginal recurrences from endometrium and cervix cancer. Furthermore, real-time US guided brachytherapy for cervix cancer is being increasingly applied using the abdominal [74], intravaginal or the trans-rectal approach [75] or any combinations. Advanced interventional radiological techniques using real-time CT or MR imaging is being applied for targeting of primary and metastatic liver tumors [76]. Pre-planning imaging is performed to plan the number of catheters to be inserted, and real-time needle guidance can be performed under the aid of dynamic MR or CT imaging. With these minimally invasive techniques, even more sites can be approached through brachytherapy such as liver, retroperitoneal space, kidney, deep seated head and neck as well as sarcomas. For intraluminal bronchial and esophageal brachytherapy endoscopy is the method of choice to place the applicator appropriately, partly complemented by radiographic and/or volumetric imaging [48]. The proximal and distal tumor length as well as the circumferential tumor

2.2.5. Image based treatment planning With the advances in 3D imaging and image based target and organ definition, the grounds were laid for significant advances in treatment planning. The detailed assessment of the 3D dose distribution has allowed for new approaches in prescribing and reporting doses for the tumor targets as well as for organs at risk. From the 3D dose distribution, dose volume histogram (DVH) parameters are now extracted which quantify the absolute or relative amount of a certain volume irradiated to a certain dose [2]. In this way, hot spots in organs at risk (e.g. D2cm3) or target periphery dose (D90) or central dose (D50) can be evaluated [2]. The clinical

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2.2.4. Developments of applicators Development of specific applicators was from the beginning in the forefront of advancing brachytherapy. Over the years special applicators and templates with certain predefined geometry of radioactive sources were developed based on large clinical experience to accommodate different clinical scenarios such as the Stockholm, Manchester and Paris system [49]. The development of image guided adaptive brachytherapy with its conceptual separation of the brachytherapy target from the brachytherapy technique has provided a new platform for applicator development. In prostate cancer the geometric coupling of transrectal ultrasound with a template for transperineal needle implantation has allowed for highly individualized implantation technique where the implant is being constructed during the procedure itself [81]. One of the first ingenuities in cervix cancer was the invention of the so-called tumor map [82] which defines the most likely topography of a tumor at time of brachytherapy in relation to the applicator. Based on the tumor map it was possible to define optimal needle tracks in terms of angulation and insertion points for transvaginal interstitial brachytherapy combined with the traditional intracavitary technique (Fig. 6). By applying this target-based method it has been possible to develop population based commercial applicators capable of handling most of the tumors seen in the clinic [83,84]. One step further is now being implemented based on the new 3D printing technology. Highly individualized templates can now be produced in a few days at an affordable price allowing for single use. These templates are is especially needed in narrow anatomical conditions not allowing for the application of the commercially available applicators. The clinical workflow, which is currently being implemented in a few departments for cervix cancer brachytherapy, involves a preplanning session where an MRI with a small intracavitary tandem and ring applicator in situ is obtained (Fig. 7) [85]. After contouring of the brachytherapy target and the organs at risk there is possibility for applying both straight and oblique needles and to individualize at the patient level the optimal insertion point and angulation. Customized software bridging the step from the treatment planning software is used allowing for direct printing in 3D in MRI compatible material approved for clinical use. It is foreseeable that future commercially available treatment planning systems will have inbuilt features for computer aided design and direct communication with a 3D printer. The example shown in Fig. 8 for cervix cancer is readily transferable to other clinical sites where imaging and 3D target definition and treatment planning of brachytherapy is being used. It supplies brachytherapy with even greater possibilities for obtaining the optimal dose distribution based on individualized brachytherapy applicators. Thus, applicator development based on 3D printing of templates could be relevant in many sites where individualized needle guidance is needed such as head and neck, anal, vaginal, endometrial and recurrent gynecological cancer.

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growth can be determined accurately, whereas for the determination of the tumor depth volumetric imaging is needed (CT, MRI, US). Guidance of brachytherapy needle insertion under laparoscopy can also be considered as a real time image procedure, which has so far mainly be reported in bladder [77,78], rectum [79], as well as trans-perineal and vaginal interstitial techniques [80].

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2.2.2. Image modalities for adaptive and individualized brachytherapy The choice of imaging for brachytherapy planning is a complex function of the best imaging for: 1) assessment of tumor, OARs, and applicators, 2) accessibility to the imaging device, 3) feasibility of imaging with applicator in place, 4) burden to the patient, and 5) the cost of imaging. CT, MR, PET, and US have been and are the major image modalities for treatment planning in radiation oncology. CT has been the dominant imaging modality so far, in particular for external beam radiotherapy, but the role of MRI and PET CT is increasing at present, both for external beam radiotherapy [70] and brachytherapy. Given the requirements for imaging for response adaptive brachytherapy, MRI has in general major advantages in terms of the excellent soft tissue contrast needed for example for discrimination of GTV and CTV in cervix cancer [71]. The current standard of care for prostate brachytherapy simulation and treatment planning is transrectal ultrasound (TRUS) imaging. However, as MRI evolves with general acceptance for staging of the intraprostatic dominant lesions, and extracapsular extension of disease [72], MRI simulation and treatment planning are emerging as active areas of investigation [73].

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clinical research. For rectal cancer there is a large variation in individual tumor response as seen in recent clinical and (multiparametric) imaging investigations [68]. An adaptive volume approach with boosting limited volumes as an organ conserving treatment option may even represent an alternative to radical mutilating surgery [69].

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2.2.6. Developments within treatment delivery verification Verification in radiation therapy means the whole process of proof that planned dose is delivered to the patient within a specific level of accuracy. During the last two decades enormous developments and technological innovations in the field of EBRT treatment verification have taken place. These developments have focused on imaging technologies for 2D, 3D and 4D localization and anatomy reconstruction under treatment delivery conditions: flat panel detectors (2D), cone beam CT (3D) [89], and most recently MRI (4D) [70]. In contrast, onboard or real-time treatment verification of BT is still not routinely performed, because adequate tools are not commercially available [90]. There is therefore a current unbalance between the availability of

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treatment verification technology for EBRT and brachytherapy, which is enhanced by the fact that brachytherapy is related with higher risk of major dose misadministration than EBRT, since brachytherapy involves: 1) more manual procedures (e.g. assembly and implantation of applicators, catheter reconstruction, and source guide tube connection), 2) mechanical equipment with a higher susceptibility to malfunction (e.g. source cable drives, tubes and applicators), 3) more frequent application of hypo-fractionation schedules with large doses per fraction, and finally 4) steeper dose gradients. Developments in treatment delivery verification are therefore currently highly warranted. Several promising technologies have emerged during the last year's opening a window to automation, real-time verification and improved verification of applicator geometry. Treatment planning is currently a process which takes e.g. 30 min-2 h including image transfer, contouring and treatment planning. Since organ and catheter movements may occur on time scales of less than 1 h, the delivered dose may not be identical to planned dose [91]. If imaging is performed directly before treatment delivery these uncertainties can be reduced. Initiatives with onboard imaging such as flat-panel or CBCT imaging are ongoing, and furthermore the first initiatives to build integrated MRI-delivery rooms are emerging [92]. Other automated treatment verification tools are electromagnetic [93] or MRI based tracking of catheters [94] as well as in vivo dosimetry [90,95].

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relevance of DVH parameters is currently being demonstrated in a wealth of studies which are demonstrating dose and effect relationships for both targets and normal tissues, in particular in prostate and gynecological cancer [86,87,26,88,25]. With the progress of clinical dose–effect evidence, it is now possible to develop evidence based dose prescription protocols which define dose planning aims as well as priorities for fulfilling hard and soft dose constraints for targets and the different organs at risk. Prescription protocols are the basis of performing dose optimization in brachytherapy, where an individualized dose prescription can be carried out based on the best balance between target and organ dose for the individual patient.

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Fig. 6. Cervix cancer patient stage IVA with bladder invasion. A) Transversal MRI with initial GTV (red). B) Transversal MRI acquired at the time of brachytherapy after delivery of EBRT. Significant tumor regression has occurred and an adaptive target contouring has been performed according to risk of recurrence: residual GTV (magenta), residual high risk CTV (red) and intermediate CTV (pink). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 7. Tumor probability map in cervix cancer based on analysis of 264 patients. The probability of presence of target volume (CTVHR) is indicated by the intensity of the gray-scale with bright white corresponding to all patients having presence of tumor and black being 0% presence. The brachytherapy applicator is indicated with green while the red contour indicates the prescription isodose. Green, blue and cyan contours indicate the volumes encompassing 75%, 95%, and 100% of the tumor voxels. A) The 75% volume (green) can be encompassed by an intracavitary dose distribution (A), while intracavitary combined with interstitial needles is needed to cover the 95% volume (blue). In the last 5% of tumor voxels, advanced applicators with oblique needles are required for appropriate dose coverage. Courtesy Primoz Petric, the Institute of Oncology, Ljubljana, Slovenia. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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Fig. 8. Workflow for design, production and use of a 3D printed vaginal template in locally advanced cervical cancer: (A) Preplanning of virtual needle positions and tracks based on T2 weighted 3 T MRI scan with a tandem-ring applicator in situ (BT0). (B) Design of the virtual template in SolidWorks based on DICOM information transferred from BrachyVision™. (C) Dummy run assembly and subsequent autoclaving of the 3D printed vaginal template. (D) Implant performed for BT1. A second implant (BT2) using the same template was performed one week later. Reproduced from [85].

Future developments in brachytherapy will happen on multiple frontiers. This section focus on 7 items of importance for improved clinical outcome and improved utilization of brachytherapy.

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2. Further integration of imaging including new image modalities. Given the focal dose distribution of brachytherapy, the accuracy of target delineation is currently a major contributor to uncertainties in the brachytherapy procedure [4]. Improved assessment of the target volume and biological tumor characteristics through functional imaging can improve the accuracy of target definition and also contribute with identification of prognostic markers. Furthermore, novel developments of interventional brachytherapy suites integrated with treatment delivery can bring real time imaging directly into the application procedure. This has potential to improve the quality of brachytherapy applications, to make it possible to reach new indications and to perform an increased amount of repeated imaging for further adaptation of target and OAR movement. Ultrasound imaging is a highly cost-effective image modality which has significant potential to spread the utilization of brachytherapy, also in cervix cancer, to environments with fewer resources. 3. Novel strategies for in situ drug delivery combined with brachytherapy. Several chemotherapy agents and other drugs are radio-sensitizers, and concomitant administration of drugs and radiotherapy is essential for disease control in many cancer sites. With the insertion of brachytherapy applicators there is a window of opportunity for exploitation of in situ drug delivery through the brachytherapy catheters, and to combine this with concomitant delivery of brachytherapy. This principle has been investigated in pre-clinical pilot studies demonstrating

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1. Further exploitation of individualized and risk adaptive treatment. Response adaptive therapy was first applied in cervix cancer, but other sites with significant tumor response during treatment (radiotherapy, chemotherapy and other therapeutic strategies) have much potential for development of similar response adaptive concepts. Treatment response is a most direct way of assessing the radiosensitivity of a tumor. Detailed response assessment should become a highly efficient predictor of disease control to be exploited for individualized adaptive treatment planning and dose prescription.

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proof of principle of modifying brachytherapy spacers into a drug eluting platform loaded with nanoparticles [96]. Further developments towards clinical implementation involves further engineering of the drug eluting systems, studies of the drug diffusion, as well as investigations of the combined effect of localized drugs delivery and brachytherapy. 4. Development of skills and expertise. Brachytherapy involves manual skills as well as expertise in disease assessment and imaging. Competences to act efficiently in a multidisciplinary team within radiation oncology, medical physics, radiology and various organ specialists are essential for the further development of brachytherapy as a major interventional (radiation) oncology procedure and to avoid the declining application of brachytherapy which is correlated with lack of skills, expertise and competence to perform such interventions. 5. Establishing clinical evidence for new technologies. The utilization of brachytherapy and implementation of new brachytherapy techniques is depending on the availability of clinical evidence. There is currently almost no level 1 evidence available with regard to the benefit of new brachytherapy technologies such as new applications of imaging and novel brachytherapy applicators. It is challenging to establish funding for technology oriented clinical trials and furthermore, randomized trials are often not suitable for assessment of the impact of steady technological progress. Large prospective multicenter trials may be more efficient in establishing benchmarks of excellent brachytherapy which can become strong arguments for dissemination of new technologies. Establishment of international brachytherapy consortia and research groups can facilitate these developments. 6. New indications and further utilization of brachytherapy in existing indications. The overall improvements in 1) imaging/interventional radiology, 2) concepts of target definition, 3) brachytherapy applicators, 4) treatment planning, and 5) dose delivery have significant potential to make brachytherapy more attractive in sites which are not yet fully exploited. With current developments towards more focal therapy, adaptive radiotherapy and hypofractionation, brachytherapy is becoming an increasingly attractive modality, e.g. for increased utilization in sites such as bladder, rectum, liver and prostate cancer. High expertise and potential centralization are key issues to

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overcome barriers towards the invasiveness of brachytherapy as opposed to EBRT which is entirely non-invasive. 7. Cost effectiveness. Increased attention to cost effectiveness is likely to make brachytherapy an increasingly attractive modality. Studies from Unites States indicate that prostate brachytherapy is cost effective as compared to IMRT and surgery [97,98], and although cost effect varies across countries, this may become of significant impact on the utilization of brachytherapy in prostate cancer in other countries as well. Furthermore, a recent cost effect analysis in cervix cancer indicates that image guided brachytherapy is cost effective [99], which may also help dissemination of this advanced technique.

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