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Innovative Technologies in Radiation Therapy: Brachytherapy
Innovative Technologies in Radiation Therapy: Brachytherapy Peter J. Hoskin, MD, FRCR, and Peter Bownes, MSc Brachytherapy has changed dramatically in the last decade, with the widespread introduction of high-dose rate afterloading systems having greater flexibility of source loading patterns and smaller sources enabling new anatomic sites to be considered. This has been harnessed to the major developments in cross-sectional imaging and dosimetry planning systems to enable highly conformal radiotherapy to be delivered accurately and reliably by brachytherapy. There has been a major change in the distribution of sites treated, the majority being prostate, gynecologic, and breast treatments, whereas an emerging role as a simple but effective palliative treatment in bronchus, esophagus, and rectal cancers has also been recognized. Semin Radiat Oncol 16:209-217 © 2006 Elsevier Inc. All rights reserved. KEYWORDS brachytherapy, afterloading, prostate, gynaecology, breast
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rachytherapy is a fundamental component of modern radiotherapy but has its roots in the earliest development of radiation therapy when radium sources were used to deliver local radiation. Brachytherapy refers to the delivery of radiation directly into or on the surface of the area of interest to be treated, being derived from the Greek word meaning “near ” or “close to.” Sources can be used in body cavities (eg, the uterus, vagina, bronchus, esophagus, and rectum), can be placed on the surface of tumors in the skin and may be placed directly into a tissue by interstitial techniques as used in the head and neck region, prostate, and breast. This review will concentrate on recent changes in the practice of brachytherapy. These should not be seen in isolation because current brachytherapy practice reflects changes in other areas (eg, a reduction in head and neck brachytherapy because of improved surgical skills and reconstructive techniques matched by a resurgence of interest in prostate brachytherapy facilitated by accurate image-guided source placement and partial breast brachytherapy reflecting changing disease biology with the greater impact of screening programs identifying small, low-risk tumors).
Mount Vernon Cancer Centre, Middlesex, United Kingdom. Address reprint requests to P.J. Hoskin, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2Rn, UK. E-mail: [email protected]
1053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2006.04.003
Brachytherapy Developments The dramatic advances in technology in the last 2 decades have impacted on the practice of brachytherapy in 2 main areas: treatment delivery and treatment planning.
Delivery Changes in brachytherapy treatment delivery have evolved partly through changes in the source availability and a widespread move from manual systems to remote afterloading systems. In developed countries, radium is no longer used, and cesium sources are increasingly being decommissioned to be replaced by high– dose rate (HDR) iridium 192 afterloading machines. The change from low– and medium– dose rate systems delivering a radiation dose at dose rates of around 1 to 1.5 Gy/h to HDR systems delivering dose at a similar dose rate to a modern linear accelerator, around 1 Gy/min, has resulted in important changes in the way in which brachytherapy is used. Radiobiologically, the change from low dose rates to HDR requires a reduction in overall dose and fractionation. Fractionation introduces logistic problems for brachytherapy because multiple treatment exposures of HDR radiation at least several hours apart require either repeat implant procedures or a very stable, carefully verified implant remaining in situ for the duration of the fractionated treatment. Appropriate dose reductions have also been required, and the considerable range of schedules used for HDR brachytherapy reflects the uncertainty in this area. Advances have certainly been made in radiobiological modeling based on the linear qua209
210 dratic equation with corrections for implant inhomogeneity being proposed,1 but robust clinical datasets, particularly focusing on late normal tissue reactions, are sparse. The scientific basis of HDR brachytherapy dose schedules therefore is often limited and based as much on pragmatism as radiobiology. The use of fractionated schedules also introduces organizational changes requiring intensive input from a range of specialties including physicians, radiographers, and physicists on an intermittent basis that can be difficult to schedule within a departmental workload. In an attempt to overcome the potential radiobiological disadvantage of HDR, pulsed dose rate machines were developed. These use the technology of an HDR afterloader with a HDR iridium source and then seek to simulate the delivery of low or medium dose rate radiation by pulsed exposures of relatively small doses, typically delivered every hour over a 24-hour period. Such systems have not gained great popularity partly because of uncertainty regarding the radiobiology of such a process that delivers intermittent HDR effects seeking to simulate continuous low dose rate effects and in addition because of regulatory requirements in many countries demanding access to a physician during source exposure, which creates significant problems for small centers in which exposure throughout a 24-hour period is being undertaken. One advantage of the iridium HDR source is that, having a high specific activity, it is physically small, typically no more than 2 mm outside diameter. This has opened up considerable possibilities for brachytherapy not readily achieved with the larger cesium sources that preceded them. Thus, smallbore catheters can be readily introduced into the bronchus, esophagus, and biliary tree to deliver intraluminal brachytherapy, and interstitial catheters can be used in the head and neck region, breast, and prostate for interstitial implant in the same way that iridium wire has been used in the past. A further important development in parallel with the changes in source technology has been the dramatic improvements in imaging quality and access. The developments in prostate brachytherapy are largely because of the ability with real-time transrectal ultrasound-guided techniques to place sources accurately within the prostate gland.
Planning Until recently, brachytherapy planning and dosimetry was based on fixed rules and fixed source geometries to achieve dose homogeneity within a planned volume. This was often based on the traditional schools of Manchester dosimetry and the Paris rules for interstitial therapy, which had served well for many years.2 Often, however, they could not be fulfilled completely and even the most experienced brachytherapist will not always achieve a perfect implant with consequent adverse effects on dosimetry. The basis of gynaecological brachytherapy has for many years been the use of Point A prescription points and organ-at-risk dosimetry limited to the International Commission on Radiation Units (ICRU) rectal and bladder point estimates. Although a pragmatic
P.J. Hoskin and P. Bownes approach, this is now seen to be anachronistic in the modern era of 3-dimensional imaging and the conventions of external-beam radiotherapy defining clinical target volumes, planning target volumes, and organs at risk are slowly being embraced by brachytherapy also. This is only feasible when cross-sectional imaging can be applied both for implant planning and postimplant dosimetry, but the added accuracy and flexibility of dose distribution more than justify the additional scanning procedures. As fixed rules have been replaced by cross-sectional and 3-dimensional planning, increased sophistication in software systems and algorithms has evolved. Computer-assisted dose calculations around a brachytherapy implant are generally now based on the American Association of Physicists in Medicine Task Group 43 (TG43 3 and TG43U 4) formalism. This formalism calculates the dose to a point in water from a single source, and if multiple sources are used, then the contribution from all sources is calculated. Treatment-planning computers have allowed the user to visually evaluate brachytherapy plans in 2- and 3-dimensional dose distributions. HDR iridium 192 afterloading units offer greater flexibility to dose planning because the stepping-source technology offers 2 degrees of freedom while planning. Once the applicators or catheters are positioned, then the planning system can manipulate not only the stopping position of the source (dwell position) but also the amount of time the source remains in each dwell position. The dose distribution can therefore be optimized to meet the planning aims for each individual implant. The other recent technological advance is the development of 3-dimensional image-based treatment-planning systems. The more advanced systems on the market allow full imagebased manipulation (including image fusion), contouring tools, and automated catheter reconstruction. Three-dimensional imaging using computed tomography (CT) scans, magnetic resonance imaging (MRI), ultrasound, or a combination of 2 modalities through image fusion has allowed for accurate target and critical organ delineation and improved applicator or source localization. Computer-based dose optimization both volumetric and geometric are available commercially along with interactive graphical dose optimization. Optimization algorithms can be used to customize and improve the dose distribution in terms of conformity, homogeneity, and reduction of critical organ doses. It is important to remember that the underlying factor to obtaining the desired dose distribution is the initial geometric placement of the catheters within the target volume. Optimization algorithms were fully covered in previous articles.5,6 For 3-dimensional image-based brachytherapy, optimization is performed on the volume. A series of volumetric dose constraints for both the target volume and the critical organs can be defined and a series of dose points placed within the defined volumes, as shown in Figure 1. This creates an inverse planning scenario in which the optimization algorithm manipulates the dwell times until the planning aims are met. A mathematically optimized plan, however, may not always represent the optimum plan and may require minor manual adjustments by the planner or dwell time gra-
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Figure 1 Plan optimization. (Color version of figure is available online.)
dient smoothing, which suppresses the dwell time gradient between neighboring dwell positions to avoid excessive hot and cold spots. All plans must be evaluated against the planning aims. This should include visual evaluation of 2-dimensional and 3-dimensional dose distributions along with assessment of dosevolume histograms and dosimetric indices. A more comprehensive discussion of the use of dose-volume histograms and dosimetry indices were covered in previous articles.7-12 It is important to evaluate the plan by considering the following: (1) How well is the distribution covering the target? (2) How homogeneous is the dose distribution throughout the volume? and (3) What dose is given to the critical structures? Three-dimensional image based brachytherapy along with advancements in computerized optimization algorithms allow a highly conformal treatment delivery.
Specific Sites Prostate Early experience with prostate brachytherapy in the 1960s was disappointing largely because of the difficulties of achieving an accurate uniform implant by the suprapubic route, which was in common use then without image guidance. Prostate brachytherapy is now widespread across the world and one of the main treatment options for men presenting with early localized prostate cancer. In many countries including the United States, prostate implants are now a serious competitor to the standard approach of radical prostatectomy. The advantages of prostate brachytherapy are those of any brachytherapy technique with closely con-
formed high-dose radiation delivery to the site of interest and low dose to organs at risk. There is now an extensive literature on the subject of prostate brachytherapy, showing its efficacy and the spectrum of side effects to be expected. Two techniques are in use. Permanent implantation with radioactive seeds is the first technique. The most common isotope is I125 which, with a half-life of 59 days delivers treatment by low-dose rate effect, the usual prescription to the PTV isodose being 145 Gy. Palladium (Pd 103) is also used in some centers. It delivers higher-dose rate radiation with a half-life of 17 days, and at one time was proposed as more appropriate for high-grade tumors, although this theory has never been proven. The renaissance for prostate seed brachytherapy occurred in the early 1980s. The basis of the technique of transperineal implantation developed then13 remains, but continued technological developments have improved the accuracy of the procedure. In particular, seed technology has been developed to improve the visibility of seeds with ultrasound imaging, and most centers now use stranded seeds rather than loose seeds, the seeds being introduced in fixed formats of seeds embedded in dissolvable suture material at 10-mm spacing. This has been shown to improve the implant quality and geometry and also facilitates loading of needles before implantation. Alongside this, there have been dramatic improvements in planning software systems for prostate seed brachytherapy. The original procedure used a 2-stage technique still in use by some departments but largely superseded by online real-time planning at the time of implantation to define seed placement and dosimetry. The original 2-stage technique10,13 allows the brachyther-
212 apy team to formulate a treatment plan a few days or weeks before the procedure. The plan will ensure coverage of the entire target volume by the prescribed dose while keeping the rectal and urethral doses within acceptable tolerances. The plan should also minimize dose inhomogeneity and assess the technical suitability of the implant. The most common approach to seed distribution is to use the “modified peripheral loading technique,” which is when some of the seeds in a uniformly loaded plan are removed to reduce the central urethra dose. Commercial planning systems now allow auto placement of seeds under strict placement rules or by dose optimization. The historic 2-step procedure has a number of potential disadvantages: it requires a separate transrectal ultrasound volume study under anesthesia; the target volume may change shape and size between the preplan volume study and the implant procedure, which may introduce inaccuracies in the implant when based on the preplan; and the patient positioning for the 2 procedures is crucial and relies on the skill of the oncologist/urologist to reproduce accurately the position of the patient at the implant stage. This can occasionally be difficult to replicate leading to possible inaccuracies or technical complications. To overcome these disadvantages, the American Brachytherapy Society recommends the following: “Ideally, one should strive for on-line, real-time intraoperative dosimetry to allow for adjustments in seed placement to achieve the intended dose.”14 Intraoperative planning is defined as “treatment planning in the OR; the patient and TRUS probe are not moved during the time between the volume study and seed insertion procedure.”15 The planning process may take the form of a preplan, in which the plan is created in the operating room just before the implant procedure, with immediate implementation of the plan. Stepwise refinement of the plan during the implant procedure as a result of needle position feedback is known as “interactive planning.” Postimplant dosimetry is an important part of the overall procedure to check the dose distribution achieved for each patient. This is normally performed by using CT or MRI at some interval after the implant, and although this calculation cannot influence the brachytherapy treatment to the individual, it is an important tool in the overall quality control of the procedure. Results from the postimplant dosimetry can be fed back to the team to help to maintain and improve service standards. Prostate brachytherapy may also be undertaken using the high-dose rate afterloading systems with a stepping iridium source. These are most commonly used as a boost treatment after external-beam radiotherapy. The delivery of large single fractions by HDR brachytherapy has gained credence with current radiobiological models that predict for a low alpha beta ratio for prostate cancer. Other potential advantages of HDR brachytherapy over seed brachytherapy are increased flexibility of the implant with the possibility of including extracapsular structures and extension into the seminal vesicals and because planning is undertaken postimplant, the catheters being placed during general anesthesia and then 3-dimensional cross-sectional imaging, usually CT based,
P.J. Hoskin and P. Bownes used to define the catheter positions followed by PTV definition, the dosimetry is more flexible, and slight changes in predicted source position can be adjusted for. It is also a temporary implant procedure with removal of the catheters at the end of the implant. In some centers in which 2 or 3 fractions are given as a boost, these may be done as separate implants but techniques for delivering successive fractions through the same implant over a period of 2 to 3 days are also in use. HDR brachytherapy is less well established than seed brachytherapy. The available clinical data, however, suggests it is highly effective, and randomized comparative data with external beam or seed brachytherapy are awaited. Case-control studies suggest it is a highly effective means of achieving dose escalation, which is known to be important in biochemical control rates for larger prostate cancers and the acute toxicity profile appears less troublesome than seed brachytherapy when acute prostatitis and severe urinary symptoms can be a problem.
Gynecological Brachytherapy The treatment of gynecologic malignancies with brachytherapy focuses mainly on cancer of the endometrium and cervix. It is used primarily in two scenarios: as primary treatment for inoperable tumors and postoperative treatment after hysterectomy for high-risk tumors. The latter remains based on intravaginal brachytherapy delivering treatment to the vaginal vault, which is a high-risk area for relapse. The major innovations have been in treatment of primary tumors in situ, again related to the move from low- and medium-dose rate systems to high-dose rate afterloading systems. The general principle of treatment using an intrauterine source, a tube or tandem, and a vaginal source in the vaginal fornix adjacent to the cervix remains unchanged. The use of HDR afterloading systems, however, introduces a number of opportunities for development away from the standard Manchester based Point A insertions. HDR brachytherapy as discussed earlier carries with it a requirement for fractionated treatments. Schedules in use for radical treatment of cervical or uterine cancer vary widely from single or 2 fraction schedules to those delivering up to 10 fractions. The most common across Europe and the United States are schedules delivering 3 or 4 fractions in addition to an external beam dose of radiotherapy delivering 45 to 50 Gy.14,15 These may be undertaken as separate implant procedures, often using spinal anesthetic or local anesthesia and heavy sedation rather than general anesthesia to facilitate this. An alternative technique has been developed by using a cervical sleeve, which is placed in situ at the first examination under anesthetic and then remains as a conduit for the intrauterine tube to be placed without anesthetic for subsequent fractions.16 The small source size and ability of the HDR afterloading cable to pass through a relatively small radius has resulted in applicator developments moving away from the standard intrauterine tube and 2 lateral vaginal sources to a tube and ring system allowing multiple source positions in the upper va-
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Figure 2 GEC ESTRO recommendations for volume definition in gynaecological brachytherapy. (Reprinted with permission.17)
gina. This immediately introduces greater flexibility for the dose distribution. With the availability of greater dose flexibility, the conventional dose prescription points based on Point A and the ICRU rectal and bladder dose points, known to be relatively poor predictors of rectal and bladder dose, have been superseded. The use of cross-sectional imaging for gynecologic brachytherapy is now recommended and described in detail in the GEC-ESTRO guidelines,7,17 which embraces the principles of high-, intermediate-, and low-risk volumes defined on CT- and MRI-based 3-dimensional imaging with the ap-
Figure 3 Conformal CT-based plan for treatment of carcinoma of the cervix. (Color version of figure is available online.)
213 plicators in situ as shown in Figure 2. MRI enables vastly superior imaging of the soft tissues in the pelvis and definition of the tumor and adjacent rectum and bladder. Thus, greater accuracy in volume definition is coupled with the greater flexibility then possible within the dosimetry-planning system to optimize the dose to the PTV and minimize dose to adjacent organs at risk. An example is shown in Figure 3. Despite the use of more sophisticated imaging and dosimetry, there are often limitations in the extent to which a midline arrangement of sources can treat a tumor that is extending laterally toward the pelvic side wall. This is unfortunately a common scenario in advanced carcinoma of the cervix. The solution to this has been to develop techniques whereby additional afterloading catheters can be placed transvaginally into the perineal tissues to enable dose to be delivered to the lateral tumor extension, which previously would not have been possible with the fixed cesium applicators. An example is shown in Figure 4. Treatment of endometrial carcinoma by primary radiotherapy using brachytherapy has presented a challenge in the past. This tumor typically occurs in obese patients with poor general health being associated with hypertension and diabetes. The uterus is typically enlarged with a dilated cavity and numerous applicators have been designed with the aim of filling the enlarged uterine cavity with sources to enable an adequate dose distribution to the uterine walls in which the tumor is found. Thus, Heyman’s capsules were developed, multistem intrauterine applicators have been used, and spring-loaded applicators to expand within the uterus also developed. The precise dosimetry of these techniques was never evaluated before the era of 3-dimensional imaging. It is
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Figure 4 CT plan showing use of an additional parametrial catheter in HDR brachytherapy for carcinoma of the cervix. (Color version of figure is available online.)
now possible using routine imaging studies to identify the uterus on a planning CT or registered MRI scan, accurately define the PTV to cover the uterine wall, and then with a single-line source intrauterine tube adjust the dwell position times to deliver an appropriate dose to the volume defined.
Breast The conventional approach to postoperative breast radiotherapy is to treat with external-beam techniques to cover the entire breast. Boosts to the tumor bed have been used using electrons or brachytherapy, and the European Organization for Research and Treatment of Cancer (EORTC) trial has shown their efficacy in reducing recurrence particularly in younger women.18 Until recently therefore, the role of brachytherapy has been limited to that of a postexternal beam boost, and in many centers electrons have been favored because of their relative efficiency and ease of administration. Furthermore, older implant techniques using freehand implantation or clinically based bridge type templates have been clumsy and often inaccurate in their coverage of the CTV. In recent years, however, there has been a surge of interest in partial-breast irradiation. This is based on an understanding that not all women have potential multifocal disease and that with widespread screening programs in developed countries a significant number of patients with very early small, low-grade tumors without associated in situ changes are being diagnosed. In addition, there are increasing concerns with regard to the late toxicity of external-beam radiotherapy in particular the induction of second tumors and cardiac damage. Against this background and coupled with the increasing availability of high-dose rate afterloading techniques, 3-dimensional imaging for accurate localization and opportunities for intraoperative implantation, partialbreast treatment after wide local excision of primary breast
tumor has gained considerable popularity. It is currently under formal evaluation in phase III trials, and its relative efficacy compared with the conventional whole breast approach has yet to be established. This approach is termed accelerated partial-breast irradiation because the treatment is delivered in a short time compared with the 5- or 6-week daily treatment required for external-beam radiotherapy. Typically, treatment will be delivered over 5 days, which may have not only radiobiological advantages but also logistic attractions for the patient. Two techniques for partial breast irradiation are in use: multicatheter brachytherapy and single-catheter (mammosite) brachytherapy. Multicatheter brachytherapy is used as a conventional brachytherapy implant covering the tumor bed with a 2- or 3-plane interstitial implant. Modern techniques use ultrasound or CT to help identify the tumor bed and postplanning dosimetry is now common for breast implants using CT reconstruction of the 3-dimensional volume. Dose prescriptions vary, a common schedule being 3.4 Gy twice daily for 5 days to deliver a total of 34 Gy. This is the basis of randomized trials in both the United States and Europe. Other schedules have used 32 Gy in 8 fractions or 38.4 Gy in 7 fractions. The current Radiation Therapy Oncology Group (RTOG) protocol uses 3.85 Gy twice daily in 10 fractions over 5 days.19,20 The alternative single-catheter technique uses a new applicator marketed as the mammosite. This is essentially a single-line flexible HDR afterloading catheter with an inflatable balloon at the end. This can be placed intraoperatively or in the first few days postoperatively into the excision cavity. The balloon is expanded with water to comfortably fill the cavity. The balloon can be inflated to a size of 65 mL. An adequate thickness of skin overlying the balloon is important to reduce late skin changes. The pro-
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Table 1 Symptom Response Rates After Intraluminal Brachytherapy Endoesophageal Endobronchial Endorectal (%) (%) (%) Obstruction Pain Bleeding
66 43 71
87 64
cedure has potential advantages of accurate placement within the tumor bed at or close to the time of surgery with a single applicator and simple dosimetry based on a singleline source with variable dwell positions. Typically, treatment is delivered over 5 days treating twice daily with the catheter remaining in situ delivering a total dose of 34 Gy. Early data on toxicity and local control rates suggest it is at least equivalent to the conventional multicatheter implant; more mature data and randomized comparative data with other techniques are required.21 One potential disadvantage is the additional cost of the mammosite catheter, which is for single use and disposable.
Palliative Brachytherapy Palliative brachytherapy has been limited by access of anatomic sites to relatively large sources for which anesthetic is often required limiting its use in the palliative setting. The development of HDR afterloading with small source sizes and flexible plastic afterloading catheters has allowed its development, particularly with intraluminal brachytherapy treating tumors of the esophagus, bronchus, and rectum in noncurative settings. The techniques for intraluminal brachytherapy are relatively simple, a bronchial catheter being introduced at the time of fiberoptic bronchoscopy, an esophageal catheter being passed with a nasogastric tube, and a rectal catheter being passed in the same way as a sigmoidoscope. It enables single-step procedures to be undertaken typically delivering doses of 10 to 15 Gy when there are troublesome symptoms from intraluminal tumor (eg, bleeding, obstruction, and pain). It is effective in all 3 of these settings, and the response rates to common symptoms are shown in Table 1. One randomized controlled trial has compared endobronchial brachytherapy with external beam in the palliative setting.21 External-beam treatment was found to be superior for the control of dyspnoea and pain, but endobronchial brachytherapy was effective in other settings although not superior to external beam. A randomized study of endoesophageal brachytherapy compared with intraluminal stenting, electrocoagulation, and ethynol injections showed that it was equivalent to the use of a self-expanding metal stent in palliation of dysphagia and pain and both of these were superior to other approaches.22 No randomized comparison of rectal brachytherapy for palliation has been undertaken, but effective control of pain and bleeding can be achieved as shown previously.23
Future Developments for Brachytherapy Brachytherapy is set to continue its development embracing in particular the advances in imaging and computer dosimetry capabilities.
Imaging Recent recommendations17 have confirmed the role of a sectional imaging– based approach, preferably with MRI, instead of the traditional radiograph approach. However, although MRI offers improved accuracy of the target volume and critical structures, the brachytherapy applicators are difficult to accurately reconstruct. Most centers in Europe tend to reconstruct the applicator on CT scans or films and then register the applicator on to the MRI. In prostate brachytherapy, a CT scan is generally accepted as the “gold standard” for both permanent seed implant postplans and HDR prostate planning. However, there are inherent difficulties with target delineation because a CT scan does not adequately image the prostate gland particularly at the base and apex. Errors in defining the prostate can lead to errors in the calculated dosimetry.24,25 MRI offers improved prostate delineation26 but does not allow accurate identification of the seeds or applicators. Image fusion of CT scans and MRI is an option to improve the consistency of postimplant dosimetry and provide accurate comparisons between centers. The prostate is equally well defined on transrectal ultrasound (TRUS), and if improvements in seed visualization on ultrasound occur; then, this may permit postimplant dosimetry to be performed directly from the “operative” ultrasound. A similar technique for HDR temporary prostate implants is discussed by Kovacs and coworkers,9 but great care when reconstructing the applicators is required. There is considerable research in the area of functional biological imaging, in particular magnetic resonance spectroscopy imaging and positron-emission tomography. In the prostate, a raised (choline ⫹ creatine)/citrate ratio ⬎1 on MRSI is considered suggestive of an intraprostatic tumor.26-28 The clinician can then define 2 target volumes: a biological target volume and a physical target volume defined on conventional sectional imaging. Figure 5 shows an example of this in the right lower peripheral area of the prostate. HDR treatment planning can be tailored to deliver an intensity modulated map with a higher dose to the biological target volume and a lower dose to the physical target volume and may achieve this with greater accuracy and reliability than external beam IMRT as shown in Figure 5. Other functional imaging techniques can provide additional biological information (eg, blood oxygen level-dependent ( BOLD) MRI can indicate areas of low oxygen levels that may benefit from higher doses and 11C thymidine positronemission tomography can identify areas of increased proliferation).
Dosimetry The TG43 dose formalism is now regarded as the standard dosimetry formalism for brachytherapy dose calculations.
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velopment of small high-specific activity, remote afterloading sources enabling new catheter design, and access to previously difficult anatomic sites harnessed to the revolution in cross-sectional imaging with CT and MRI being a routine part of the implant evaluation feeding into evermore sophisticated treatment-planning algorithms enables precision high-dose conformal radiotherapy to be delivered through modern brachytherapy techniques.
References
Figure 5 Plan for HDR prostate brachytherapy showing potential for biological subvolume definition and treatment. (Color version of figure is available online.)
Current planning systems assume the medium around the source is water and compute a dose to water. The next generation of 3-dimensional dose calculation methods in brachytherapy needs to be able to deal with tissue inhomogeneities, finite human body dimensions, applicator material, and shielding materials if used. Monte Carlo techniques would be the gold standard for 3-dimensional dose calculations. However, current clinical treatment planning systems do not have the computer power/speed to support Monte Carlo. There is a shift of importance in treatment planning to move to 3-dimensional image-based intraoperative planning. For this to be successful, the software has to be fast and accurate and the user must be able to easily interact, guide, and evaluate the plan. To be able to achieve both speed for intraoperative planning and calculation accuracy, Monte Carlo calculations may have to be simplified with look-up tables to achieve both goals.29 Bioeffect dose modeling is of considerable interest and generally has been used for research purposes. Further work is required before it can be incorporated into clinical planning, but it could have a valuable impact when a treatment regimen includes two modalities.30
Summary In the past decade, there have been major technical innovations in the field of brachytherapy that have revolutionized its use in the management of patients with malignant disease. It is now at the forefront of radiation therapy for prostate cancer, breast cancer, and gynecologic cancers. It has a major role in palliative treatments for lung, esophagus, and rectal cancers. It has, of course, many other applications and still retains a place in the treatment of head and neck cancer, penile cancer, biliary duct cancer, and skin cancers. The de-
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trolled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer. Health Technol Assess 9:1-100, 2005 Al-Qaisieh B, Ash D, Bottomley DM, et al: Impact of prostate volume evaluation by different observers on CT-based post-implant dosimetry. Radiother Oncol 62:267-273, 2002 Al-Qaisieh B: Pre- and post-implant dosimetry: an inter-comparison between UK prostate brachytherapy centres. Radiother Oncol 66:181183, 2003 Villiers GM, Vestraete KL, De Neve WJ, et al: Magnetic Resonanceimaging anatomy of the prostate and periprostatic area: A guide for radiotherapists. Radiother Oncol 76:99-106, 2005 Ling LL, Leibel S, Fuks Z, et al: in Memorial Sloan-Kettering Cancer Center (eds): A practical guide to intensity-modulated radiation therapy. Madison, Wisconsin, Medical Physics Publishing, 2003 Zelefsky MJ: Incorporating Functional Imaging with Prostate Brachytherapy, GEC-ESTRO–ABS-GLAC Joint Brachytherapy Workshop— Advances in Image Based Brachytherapy, Barcelona, May 13-15, 2004 Baltas D, Anagnostopoulos G, Milickovic N: 3D Imaging based treatment planning in brachytherapy, the next generation or what next to TG-43. Radiother Oncol 71:29, 2004 (suppl 2, abstr) Dale R: The role of radiobiology in the management of cervix cancer. Radiother Oncol 71:101, 2004 (suppl 2, abstr)
B
rachytherapy is a fundamental component of modern radiotherapy but has its roots in the earliest development of radiation therapy when radium sources were used to deliver local radiation. Brachytherapy refers to the delivery of radiation directly into or on the surface of the area of interest to be treated, being derived from the Greek word meaning “near ” or “close to.” Sources can be used in body cavities (eg, the uterus, vagina, bronchus, esophagus, and rectum), can be placed on the surface of tumors in the skin and may be placed directly into a tissue by interstitial techniques as used in the head and neck region, prostate, and breast. This review will concentrate on recent changes in the practice of brachytherapy. These should not be seen in isolation because current brachytherapy practice reflects changes in other areas (eg, a reduction in head and neck brachytherapy because of improved surgical skills and reconstructive techniques matched by a resurgence of interest in prostate brachytherapy facilitated by accurate image-guided source placement and partial breast brachytherapy reflecting changing disease biology with the greater impact of screening programs identifying small, low-risk tumors).
Mount Vernon Cancer Centre, Middlesex, United Kingdom. Address reprint requests to P.J. Hoskin, Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, Middlesex HA6 2Rn, UK. E-mail: [email protected]
1053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2006.04.003
Brachytherapy Developments The dramatic advances in technology in the last 2 decades have impacted on the practice of brachytherapy in 2 main areas: treatment delivery and treatment planning.
Delivery Changes in brachytherapy treatment delivery have evolved partly through changes in the source availability and a widespread move from manual systems to remote afterloading systems. In developed countries, radium is no longer used, and cesium sources are increasingly being decommissioned to be replaced by high– dose rate (HDR) iridium 192 afterloading machines. The change from low– and medium– dose rate systems delivering a radiation dose at dose rates of around 1 to 1.5 Gy/h to HDR systems delivering dose at a similar dose rate to a modern linear accelerator, around 1 Gy/min, has resulted in important changes in the way in which brachytherapy is used. Radiobiologically, the change from low dose rates to HDR requires a reduction in overall dose and fractionation. Fractionation introduces logistic problems for brachytherapy because multiple treatment exposures of HDR radiation at least several hours apart require either repeat implant procedures or a very stable, carefully verified implant remaining in situ for the duration of the fractionated treatment. Appropriate dose reductions have also been required, and the considerable range of schedules used for HDR brachytherapy reflects the uncertainty in this area. Advances have certainly been made in radiobiological modeling based on the linear qua209
210 dratic equation with corrections for implant inhomogeneity being proposed,1 but robust clinical datasets, particularly focusing on late normal tissue reactions, are sparse. The scientific basis of HDR brachytherapy dose schedules therefore is often limited and based as much on pragmatism as radiobiology. The use of fractionated schedules also introduces organizational changes requiring intensive input from a range of specialties including physicians, radiographers, and physicists on an intermittent basis that can be difficult to schedule within a departmental workload. In an attempt to overcome the potential radiobiological disadvantage of HDR, pulsed dose rate machines were developed. These use the technology of an HDR afterloader with a HDR iridium source and then seek to simulate the delivery of low or medium dose rate radiation by pulsed exposures of relatively small doses, typically delivered every hour over a 24-hour period. Such systems have not gained great popularity partly because of uncertainty regarding the radiobiology of such a process that delivers intermittent HDR effects seeking to simulate continuous low dose rate effects and in addition because of regulatory requirements in many countries demanding access to a physician during source exposure, which creates significant problems for small centers in which exposure throughout a 24-hour period is being undertaken. One advantage of the iridium HDR source is that, having a high specific activity, it is physically small, typically no more than 2 mm outside diameter. This has opened up considerable possibilities for brachytherapy not readily achieved with the larger cesium sources that preceded them. Thus, smallbore catheters can be readily introduced into the bronchus, esophagus, and biliary tree to deliver intraluminal brachytherapy, and interstitial catheters can be used in the head and neck region, breast, and prostate for interstitial implant in the same way that iridium wire has been used in the past. A further important development in parallel with the changes in source technology has been the dramatic improvements in imaging quality and access. The developments in prostate brachytherapy are largely because of the ability with real-time transrectal ultrasound-guided techniques to place sources accurately within the prostate gland.
Planning Until recently, brachytherapy planning and dosimetry was based on fixed rules and fixed source geometries to achieve dose homogeneity within a planned volume. This was often based on the traditional schools of Manchester dosimetry and the Paris rules for interstitial therapy, which had served well for many years.2 Often, however, they could not be fulfilled completely and even the most experienced brachytherapist will not always achieve a perfect implant with consequent adverse effects on dosimetry. The basis of gynaecological brachytherapy has for many years been the use of Point A prescription points and organ-at-risk dosimetry limited to the International Commission on Radiation Units (ICRU) rectal and bladder point estimates. Although a pragmatic
P.J. Hoskin and P. Bownes approach, this is now seen to be anachronistic in the modern era of 3-dimensional imaging and the conventions of external-beam radiotherapy defining clinical target volumes, planning target volumes, and organs at risk are slowly being embraced by brachytherapy also. This is only feasible when cross-sectional imaging can be applied both for implant planning and postimplant dosimetry, but the added accuracy and flexibility of dose distribution more than justify the additional scanning procedures. As fixed rules have been replaced by cross-sectional and 3-dimensional planning, increased sophistication in software systems and algorithms has evolved. Computer-assisted dose calculations around a brachytherapy implant are generally now based on the American Association of Physicists in Medicine Task Group 43 (TG43 3 and TG43U 4) formalism. This formalism calculates the dose to a point in water from a single source, and if multiple sources are used, then the contribution from all sources is calculated. Treatment-planning computers have allowed the user to visually evaluate brachytherapy plans in 2- and 3-dimensional dose distributions. HDR iridium 192 afterloading units offer greater flexibility to dose planning because the stepping-source technology offers 2 degrees of freedom while planning. Once the applicators or catheters are positioned, then the planning system can manipulate not only the stopping position of the source (dwell position) but also the amount of time the source remains in each dwell position. The dose distribution can therefore be optimized to meet the planning aims for each individual implant. The other recent technological advance is the development of 3-dimensional image-based treatment-planning systems. The more advanced systems on the market allow full imagebased manipulation (including image fusion), contouring tools, and automated catheter reconstruction. Three-dimensional imaging using computed tomography (CT) scans, magnetic resonance imaging (MRI), ultrasound, or a combination of 2 modalities through image fusion has allowed for accurate target and critical organ delineation and improved applicator or source localization. Computer-based dose optimization both volumetric and geometric are available commercially along with interactive graphical dose optimization. Optimization algorithms can be used to customize and improve the dose distribution in terms of conformity, homogeneity, and reduction of critical organ doses. It is important to remember that the underlying factor to obtaining the desired dose distribution is the initial geometric placement of the catheters within the target volume. Optimization algorithms were fully covered in previous articles.5,6 For 3-dimensional image-based brachytherapy, optimization is performed on the volume. A series of volumetric dose constraints for both the target volume and the critical organs can be defined and a series of dose points placed within the defined volumes, as shown in Figure 1. This creates an inverse planning scenario in which the optimization algorithm manipulates the dwell times until the planning aims are met. A mathematically optimized plan, however, may not always represent the optimum plan and may require minor manual adjustments by the planner or dwell time gra-
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Figure 1 Plan optimization. (Color version of figure is available online.)
dient smoothing, which suppresses the dwell time gradient between neighboring dwell positions to avoid excessive hot and cold spots. All plans must be evaluated against the planning aims. This should include visual evaluation of 2-dimensional and 3-dimensional dose distributions along with assessment of dosevolume histograms and dosimetric indices. A more comprehensive discussion of the use of dose-volume histograms and dosimetry indices were covered in previous articles.7-12 It is important to evaluate the plan by considering the following: (1) How well is the distribution covering the target? (2) How homogeneous is the dose distribution throughout the volume? and (3) What dose is given to the critical structures? Three-dimensional image based brachytherapy along with advancements in computerized optimization algorithms allow a highly conformal treatment delivery.
Specific Sites Prostate Early experience with prostate brachytherapy in the 1960s was disappointing largely because of the difficulties of achieving an accurate uniform implant by the suprapubic route, which was in common use then without image guidance. Prostate brachytherapy is now widespread across the world and one of the main treatment options for men presenting with early localized prostate cancer. In many countries including the United States, prostate implants are now a serious competitor to the standard approach of radical prostatectomy. The advantages of prostate brachytherapy are those of any brachytherapy technique with closely con-
formed high-dose radiation delivery to the site of interest and low dose to organs at risk. There is now an extensive literature on the subject of prostate brachytherapy, showing its efficacy and the spectrum of side effects to be expected. Two techniques are in use. Permanent implantation with radioactive seeds is the first technique. The most common isotope is I125 which, with a half-life of 59 days delivers treatment by low-dose rate effect, the usual prescription to the PTV isodose being 145 Gy. Palladium (Pd 103) is also used in some centers. It delivers higher-dose rate radiation with a half-life of 17 days, and at one time was proposed as more appropriate for high-grade tumors, although this theory has never been proven. The renaissance for prostate seed brachytherapy occurred in the early 1980s. The basis of the technique of transperineal implantation developed then13 remains, but continued technological developments have improved the accuracy of the procedure. In particular, seed technology has been developed to improve the visibility of seeds with ultrasound imaging, and most centers now use stranded seeds rather than loose seeds, the seeds being introduced in fixed formats of seeds embedded in dissolvable suture material at 10-mm spacing. This has been shown to improve the implant quality and geometry and also facilitates loading of needles before implantation. Alongside this, there have been dramatic improvements in planning software systems for prostate seed brachytherapy. The original procedure used a 2-stage technique still in use by some departments but largely superseded by online real-time planning at the time of implantation to define seed placement and dosimetry. The original 2-stage technique10,13 allows the brachyther-
212 apy team to formulate a treatment plan a few days or weeks before the procedure. The plan will ensure coverage of the entire target volume by the prescribed dose while keeping the rectal and urethral doses within acceptable tolerances. The plan should also minimize dose inhomogeneity and assess the technical suitability of the implant. The most common approach to seed distribution is to use the “modified peripheral loading technique,” which is when some of the seeds in a uniformly loaded plan are removed to reduce the central urethra dose. Commercial planning systems now allow auto placement of seeds under strict placement rules or by dose optimization. The historic 2-step procedure has a number of potential disadvantages: it requires a separate transrectal ultrasound volume study under anesthesia; the target volume may change shape and size between the preplan volume study and the implant procedure, which may introduce inaccuracies in the implant when based on the preplan; and the patient positioning for the 2 procedures is crucial and relies on the skill of the oncologist/urologist to reproduce accurately the position of the patient at the implant stage. This can occasionally be difficult to replicate leading to possible inaccuracies or technical complications. To overcome these disadvantages, the American Brachytherapy Society recommends the following: “Ideally, one should strive for on-line, real-time intraoperative dosimetry to allow for adjustments in seed placement to achieve the intended dose.”14 Intraoperative planning is defined as “treatment planning in the OR; the patient and TRUS probe are not moved during the time between the volume study and seed insertion procedure.”15 The planning process may take the form of a preplan, in which the plan is created in the operating room just before the implant procedure, with immediate implementation of the plan. Stepwise refinement of the plan during the implant procedure as a result of needle position feedback is known as “interactive planning.” Postimplant dosimetry is an important part of the overall procedure to check the dose distribution achieved for each patient. This is normally performed by using CT or MRI at some interval after the implant, and although this calculation cannot influence the brachytherapy treatment to the individual, it is an important tool in the overall quality control of the procedure. Results from the postimplant dosimetry can be fed back to the team to help to maintain and improve service standards. Prostate brachytherapy may also be undertaken using the high-dose rate afterloading systems with a stepping iridium source. These are most commonly used as a boost treatment after external-beam radiotherapy. The delivery of large single fractions by HDR brachytherapy has gained credence with current radiobiological models that predict for a low alpha beta ratio for prostate cancer. Other potential advantages of HDR brachytherapy over seed brachytherapy are increased flexibility of the implant with the possibility of including extracapsular structures and extension into the seminal vesicals and because planning is undertaken postimplant, the catheters being placed during general anesthesia and then 3-dimensional cross-sectional imaging, usually CT based,
P.J. Hoskin and P. Bownes used to define the catheter positions followed by PTV definition, the dosimetry is more flexible, and slight changes in predicted source position can be adjusted for. It is also a temporary implant procedure with removal of the catheters at the end of the implant. In some centers in which 2 or 3 fractions are given as a boost, these may be done as separate implants but techniques for delivering successive fractions through the same implant over a period of 2 to 3 days are also in use. HDR brachytherapy is less well established than seed brachytherapy. The available clinical data, however, suggests it is highly effective, and randomized comparative data with external beam or seed brachytherapy are awaited. Case-control studies suggest it is a highly effective means of achieving dose escalation, which is known to be important in biochemical control rates for larger prostate cancers and the acute toxicity profile appears less troublesome than seed brachytherapy when acute prostatitis and severe urinary symptoms can be a problem.
Gynecological Brachytherapy The treatment of gynecologic malignancies with brachytherapy focuses mainly on cancer of the endometrium and cervix. It is used primarily in two scenarios: as primary treatment for inoperable tumors and postoperative treatment after hysterectomy for high-risk tumors. The latter remains based on intravaginal brachytherapy delivering treatment to the vaginal vault, which is a high-risk area for relapse. The major innovations have been in treatment of primary tumors in situ, again related to the move from low- and medium-dose rate systems to high-dose rate afterloading systems. The general principle of treatment using an intrauterine source, a tube or tandem, and a vaginal source in the vaginal fornix adjacent to the cervix remains unchanged. The use of HDR afterloading systems, however, introduces a number of opportunities for development away from the standard Manchester based Point A insertions. HDR brachytherapy as discussed earlier carries with it a requirement for fractionated treatments. Schedules in use for radical treatment of cervical or uterine cancer vary widely from single or 2 fraction schedules to those delivering up to 10 fractions. The most common across Europe and the United States are schedules delivering 3 or 4 fractions in addition to an external beam dose of radiotherapy delivering 45 to 50 Gy.14,15 These may be undertaken as separate implant procedures, often using spinal anesthetic or local anesthesia and heavy sedation rather than general anesthesia to facilitate this. An alternative technique has been developed by using a cervical sleeve, which is placed in situ at the first examination under anesthetic and then remains as a conduit for the intrauterine tube to be placed without anesthetic for subsequent fractions.16 The small source size and ability of the HDR afterloading cable to pass through a relatively small radius has resulted in applicator developments moving away from the standard intrauterine tube and 2 lateral vaginal sources to a tube and ring system allowing multiple source positions in the upper va-
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Figure 2 GEC ESTRO recommendations for volume definition in gynaecological brachytherapy. (Reprinted with permission.17)
gina. This immediately introduces greater flexibility for the dose distribution. With the availability of greater dose flexibility, the conventional dose prescription points based on Point A and the ICRU rectal and bladder dose points, known to be relatively poor predictors of rectal and bladder dose, have been superseded. The use of cross-sectional imaging for gynecologic brachytherapy is now recommended and described in detail in the GEC-ESTRO guidelines,7,17 which embraces the principles of high-, intermediate-, and low-risk volumes defined on CT- and MRI-based 3-dimensional imaging with the ap-
Figure 3 Conformal CT-based plan for treatment of carcinoma of the cervix. (Color version of figure is available online.)
213 plicators in situ as shown in Figure 2. MRI enables vastly superior imaging of the soft tissues in the pelvis and definition of the tumor and adjacent rectum and bladder. Thus, greater accuracy in volume definition is coupled with the greater flexibility then possible within the dosimetry-planning system to optimize the dose to the PTV and minimize dose to adjacent organs at risk. An example is shown in Figure 3. Despite the use of more sophisticated imaging and dosimetry, there are often limitations in the extent to which a midline arrangement of sources can treat a tumor that is extending laterally toward the pelvic side wall. This is unfortunately a common scenario in advanced carcinoma of the cervix. The solution to this has been to develop techniques whereby additional afterloading catheters can be placed transvaginally into the perineal tissues to enable dose to be delivered to the lateral tumor extension, which previously would not have been possible with the fixed cesium applicators. An example is shown in Figure 4. Treatment of endometrial carcinoma by primary radiotherapy using brachytherapy has presented a challenge in the past. This tumor typically occurs in obese patients with poor general health being associated with hypertension and diabetes. The uterus is typically enlarged with a dilated cavity and numerous applicators have been designed with the aim of filling the enlarged uterine cavity with sources to enable an adequate dose distribution to the uterine walls in which the tumor is found. Thus, Heyman’s capsules were developed, multistem intrauterine applicators have been used, and spring-loaded applicators to expand within the uterus also developed. The precise dosimetry of these techniques was never evaluated before the era of 3-dimensional imaging. It is
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Figure 4 CT plan showing use of an additional parametrial catheter in HDR brachytherapy for carcinoma of the cervix. (Color version of figure is available online.)
now possible using routine imaging studies to identify the uterus on a planning CT or registered MRI scan, accurately define the PTV to cover the uterine wall, and then with a single-line source intrauterine tube adjust the dwell position times to deliver an appropriate dose to the volume defined.
Breast The conventional approach to postoperative breast radiotherapy is to treat with external-beam techniques to cover the entire breast. Boosts to the tumor bed have been used using electrons or brachytherapy, and the European Organization for Research and Treatment of Cancer (EORTC) trial has shown their efficacy in reducing recurrence particularly in younger women.18 Until recently therefore, the role of brachytherapy has been limited to that of a postexternal beam boost, and in many centers electrons have been favored because of their relative efficiency and ease of administration. Furthermore, older implant techniques using freehand implantation or clinically based bridge type templates have been clumsy and often inaccurate in their coverage of the CTV. In recent years, however, there has been a surge of interest in partial-breast irradiation. This is based on an understanding that not all women have potential multifocal disease and that with widespread screening programs in developed countries a significant number of patients with very early small, low-grade tumors without associated in situ changes are being diagnosed. In addition, there are increasing concerns with regard to the late toxicity of external-beam radiotherapy in particular the induction of second tumors and cardiac damage. Against this background and coupled with the increasing availability of high-dose rate afterloading techniques, 3-dimensional imaging for accurate localization and opportunities for intraoperative implantation, partialbreast treatment after wide local excision of primary breast
tumor has gained considerable popularity. It is currently under formal evaluation in phase III trials, and its relative efficacy compared with the conventional whole breast approach has yet to be established. This approach is termed accelerated partial-breast irradiation because the treatment is delivered in a short time compared with the 5- or 6-week daily treatment required for external-beam radiotherapy. Typically, treatment will be delivered over 5 days, which may have not only radiobiological advantages but also logistic attractions for the patient. Two techniques for partial breast irradiation are in use: multicatheter brachytherapy and single-catheter (mammosite) brachytherapy. Multicatheter brachytherapy is used as a conventional brachytherapy implant covering the tumor bed with a 2- or 3-plane interstitial implant. Modern techniques use ultrasound or CT to help identify the tumor bed and postplanning dosimetry is now common for breast implants using CT reconstruction of the 3-dimensional volume. Dose prescriptions vary, a common schedule being 3.4 Gy twice daily for 5 days to deliver a total of 34 Gy. This is the basis of randomized trials in both the United States and Europe. Other schedules have used 32 Gy in 8 fractions or 38.4 Gy in 7 fractions. The current Radiation Therapy Oncology Group (RTOG) protocol uses 3.85 Gy twice daily in 10 fractions over 5 days.19,20 The alternative single-catheter technique uses a new applicator marketed as the mammosite. This is essentially a single-line flexible HDR afterloading catheter with an inflatable balloon at the end. This can be placed intraoperatively or in the first few days postoperatively into the excision cavity. The balloon is expanded with water to comfortably fill the cavity. The balloon can be inflated to a size of 65 mL. An adequate thickness of skin overlying the balloon is important to reduce late skin changes. The pro-
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Table 1 Symptom Response Rates After Intraluminal Brachytherapy Endoesophageal Endobronchial Endorectal (%) (%) (%) Obstruction Pain Bleeding
66 43 71
87 64
cedure has potential advantages of accurate placement within the tumor bed at or close to the time of surgery with a single applicator and simple dosimetry based on a singleline source with variable dwell positions. Typically, treatment is delivered over 5 days treating twice daily with the catheter remaining in situ delivering a total dose of 34 Gy. Early data on toxicity and local control rates suggest it is at least equivalent to the conventional multicatheter implant; more mature data and randomized comparative data with other techniques are required.21 One potential disadvantage is the additional cost of the mammosite catheter, which is for single use and disposable.
Palliative Brachytherapy Palliative brachytherapy has been limited by access of anatomic sites to relatively large sources for which anesthetic is often required limiting its use in the palliative setting. The development of HDR afterloading with small source sizes and flexible plastic afterloading catheters has allowed its development, particularly with intraluminal brachytherapy treating tumors of the esophagus, bronchus, and rectum in noncurative settings. The techniques for intraluminal brachytherapy are relatively simple, a bronchial catheter being introduced at the time of fiberoptic bronchoscopy, an esophageal catheter being passed with a nasogastric tube, and a rectal catheter being passed in the same way as a sigmoidoscope. It enables single-step procedures to be undertaken typically delivering doses of 10 to 15 Gy when there are troublesome symptoms from intraluminal tumor (eg, bleeding, obstruction, and pain). It is effective in all 3 of these settings, and the response rates to common symptoms are shown in Table 1. One randomized controlled trial has compared endobronchial brachytherapy with external beam in the palliative setting.21 External-beam treatment was found to be superior for the control of dyspnoea and pain, but endobronchial brachytherapy was effective in other settings although not superior to external beam. A randomized study of endoesophageal brachytherapy compared with intraluminal stenting, electrocoagulation, and ethynol injections showed that it was equivalent to the use of a self-expanding metal stent in palliation of dysphagia and pain and both of these were superior to other approaches.22 No randomized comparison of rectal brachytherapy for palliation has been undertaken, but effective control of pain and bleeding can be achieved as shown previously.23
Future Developments for Brachytherapy Brachytherapy is set to continue its development embracing in particular the advances in imaging and computer dosimetry capabilities.
Imaging Recent recommendations17 have confirmed the role of a sectional imaging– based approach, preferably with MRI, instead of the traditional radiograph approach. However, although MRI offers improved accuracy of the target volume and critical structures, the brachytherapy applicators are difficult to accurately reconstruct. Most centers in Europe tend to reconstruct the applicator on CT scans or films and then register the applicator on to the MRI. In prostate brachytherapy, a CT scan is generally accepted as the “gold standard” for both permanent seed implant postplans and HDR prostate planning. However, there are inherent difficulties with target delineation because a CT scan does not adequately image the prostate gland particularly at the base and apex. Errors in defining the prostate can lead to errors in the calculated dosimetry.24,25 MRI offers improved prostate delineation26 but does not allow accurate identification of the seeds or applicators. Image fusion of CT scans and MRI is an option to improve the consistency of postimplant dosimetry and provide accurate comparisons between centers. The prostate is equally well defined on transrectal ultrasound (TRUS), and if improvements in seed visualization on ultrasound occur; then, this may permit postimplant dosimetry to be performed directly from the “operative” ultrasound. A similar technique for HDR temporary prostate implants is discussed by Kovacs and coworkers,9 but great care when reconstructing the applicators is required. There is considerable research in the area of functional biological imaging, in particular magnetic resonance spectroscopy imaging and positron-emission tomography. In the prostate, a raised (choline ⫹ creatine)/citrate ratio ⬎1 on MRSI is considered suggestive of an intraprostatic tumor.26-28 The clinician can then define 2 target volumes: a biological target volume and a physical target volume defined on conventional sectional imaging. Figure 5 shows an example of this in the right lower peripheral area of the prostate. HDR treatment planning can be tailored to deliver an intensity modulated map with a higher dose to the biological target volume and a lower dose to the physical target volume and may achieve this with greater accuracy and reliability than external beam IMRT as shown in Figure 5. Other functional imaging techniques can provide additional biological information (eg, blood oxygen level-dependent ( BOLD) MRI can indicate areas of low oxygen levels that may benefit from higher doses and 11C thymidine positronemission tomography can identify areas of increased proliferation).
Dosimetry The TG43 dose formalism is now regarded as the standard dosimetry formalism for brachytherapy dose calculations.
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velopment of small high-specific activity, remote afterloading sources enabling new catheter design, and access to previously difficult anatomic sites harnessed to the revolution in cross-sectional imaging with CT and MRI being a routine part of the implant evaluation feeding into evermore sophisticated treatment-planning algorithms enables precision high-dose conformal radiotherapy to be delivered through modern brachytherapy techniques.
References
Figure 5 Plan for HDR prostate brachytherapy showing potential for biological subvolume definition and treatment. (Color version of figure is available online.)
Current planning systems assume the medium around the source is water and compute a dose to water. The next generation of 3-dimensional dose calculation methods in brachytherapy needs to be able to deal with tissue inhomogeneities, finite human body dimensions, applicator material, and shielding materials if used. Monte Carlo techniques would be the gold standard for 3-dimensional dose calculations. However, current clinical treatment planning systems do not have the computer power/speed to support Monte Carlo. There is a shift of importance in treatment planning to move to 3-dimensional image-based intraoperative planning. For this to be successful, the software has to be fast and accurate and the user must be able to easily interact, guide, and evaluate the plan. To be able to achieve both speed for intraoperative planning and calculation accuracy, Monte Carlo calculations may have to be simplified with look-up tables to achieve both goals.29 Bioeffect dose modeling is of considerable interest and generally has been used for research purposes. Further work is required before it can be incorporated into clinical planning, but it could have a valuable impact when a treatment regimen includes two modalities.30
Summary In the past decade, there have been major technical innovations in the field of brachytherapy that have revolutionized its use in the management of patients with malignant disease. It is now at the forefront of radiation therapy for prostate cancer, breast cancer, and gynecologic cancers. It has a major role in palliative treatments for lung, esophagus, and rectal cancers. It has, of course, many other applications and still retains a place in the treatment of head and neck cancer, penile cancer, biliary duct cancer, and skin cancers. The de-
1. Dale RG, Jones B: The clinical radiobiology of brachytherapy. Br J Radiol 71:465-483, 1998 2. Richardson C: Principles of brachytherapy dosimetry, in Hoskin PJ, Coyle C (eds): Radiotherapy in Practice: Brachytherapy. Coyle C. Oxford University Press, Oxford, 2005, pp 21-42 3. Nath R, Anderson LL, Luxton G, et al: Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Task Group No 43. Med Phys 22:209-234, 1995 4. Rivard MJ, Coursey BM, DeWerd LA, et al: Update of AAPPM Task Group No. 43 Report: A revised AAPM protocol for brachytherapy dose calculations. Med Phys 31:633-674, 2004 5. Van Der Laarse R, Luthman RW: Computer in brachytherapy, in Joslin CAF, Flynn A, Hall EJ (eds): Principles and Practice of Brachytherapy Using Afterloading Systems. London, Arnold, 2001 6. Mould RF, Baterman JJ, Martinez AA, Speiser BL (eds): Brachytherapy From Radium to Optimistaion. The Netherlands, Nucletron International B.V, 1994 7. Potter R, Haie-Meder C, Van Limbergen E, et al: Recommendations from gynaecological (Gyn) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy—3D dose volume parameters and aspects of 3D image based brachytherapy, radiation physics, radiobiology. Radiother Oncol 78:67-77, 2006 8. Moerland MA, Van der Laarse R, Luthmann RW, et al: The combined use of the natural and the cumulative dose-volume in planning and evaluation of permanent prostatic seed implants. Radiother Oncol 57: 279-284, 2000 9. Kovacs G, Potter R, Loch T, et al: GEC/ESTRO-EAU recommendations on temporary brachytherapy using stepping sources for localised prostate cancer. Radiother Oncol 74:137-148, 2005 10. Yu Y, Anderson LL, Li Z, et al: Permanent prostate seed implant brachytherapy: Report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 26:2054-2076, 1999 11. Merrick GS, Butler WM, Wallner KE, et al: Variability of prostate brachytherapy preimplant dosimetry: A multi-institutional analysis. Brachytherapy 4:241-251, 2005 12. Baltas D, Kolotas C, Geramani K, et al: A conformal Index (COIN) to evaluate implant quality and dose specification in brachytherapy. Int J Radiat Oncol Biol Phys 40:515-524, 1998 13. Blasko JC, Grimm PD, Ragde H: Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 3:240-249, 1993 14. Nag S, Bice W, DeWyngaert K, et al: The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 46:221-230, 2000 15. Nag S, Ciezki JP, Cormack R, et al: Introperative planning and evaluation of permanent prostate brachytherapy: Report of the American brachytherapy society. Int J Radiat Oncol Biol Phys 51:1422-1430, 2001 16. Tyrie LK, Hoskin PJ: Intrauterine high dose rate afterloading brachytherapy: Experience of fractionated therapy using a cervical sleeve technique. Clin Oncol 69:671-672, 1996 17. Haie-Meder C, Potter R, Van Limbergen E, et al: Gynaecological (GYN) GEC-ESTRO Working Group. Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy
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