Low dose rate permanent seed brachytherapy: tracing its evolution and current status

A recent surge in publications on low dose rate permanent seed brachytherapy prompted us to review the currently available literature in order to provide a summary of the therapy. To this end, we composed a comprehensive review on the available English language publications in PubMed, EMBASE, and Google Scholar. The general principles of seed brachytherapy are discussed, along with radiobiology and technical aspects. Seed brachytherapy has been increasingly used in various sites for primary treatment, and is considered to be particularly useful in cases of reirradiation and otherwise untreatable malignancies. In recent decades, there have been considerable advances in the technology used in seed brachytherapy, including steps to prevent the migration of seeds, reduce personnel exposure to radiation, and use of sophisticated 3‐D planning for better dosimetric results, which have ultimately translated into better clinical outputs. Technical advances in seed brachytherapy have lagged behind those in external beam radiotherapy and high dose rate brachytherapy; however, there is renewed interest due to encouraging clinical results in the primary setting, as well as reirradiation for recurrent disease across several sites.


INTRODUCTION
Brachytherapy is the oldest radiotherapy technique, and at its outset, involved low dose rate (LDR) temporary implants that required manual application and removal; the procedures carried significant threat of radiation exposure to the patient and personnel, in addition to prolonged confinement in a shielded room and multiple applications. Therefore, further research was focused on using sources that could be placed directly into the tumor, but did not require removal; this was the origin of seed brachytherapy. The earliest published reports on seed distribution. A typical implant delivered 4000 millicurie-hours (mCi-h).
In the late 1950s and 1960s, from the same institution, Hilaris reported on the use of iodine-125 (I-125) seed brachytherapy for the treatment of sites such as lungs, prostate, pancreas, and oral cavity. Even at that time, the need for better technical solutions facilitating brachytherapy to improve its popularity over teletherapy, as well as the dosimetric advantages of I-125 over  seeds, and lesser radiation protection hazard was well identified. 2 Interestingly, Mahatma Gandhi correlated the concept of LDR with his principle of non-violence in one of his letters, "Non-violence is like radium in its action. An infinitesimal quantity of it imbedded in a malignant growth acts continuously, silently, and ceaselessly till it has transformed the whole mass of the diseased tissue into a healthy one". 3 For over a century, the use of seed brachytherapy has risen and fallen in popularity, with a general belief that high dose rate (HDR) brachytherapy would ultimately replace all other forms of brachytherapy. In recent times, there has been a renewed interest in LDR seed brachytherapy, evident by the surge of publications; indeed, a PubMed search on English language literature on "seed brachytherapy" yielded 639 publications since 2014, including clinical and technical reports. This renewed interest prompted us to review the available literature to discern its current role and status 4 .

METHODS
We did not attempt a systematic review due to the diversity of sites, indications, and methods. Instead, this review aimed to summarize the available literature on the diverse uses of seeds in clinics, and renew interest on upcoming developments in the field. Available English language literature in PubMed, EMBASE, and Google Scholar was searched using the keywords "low dose rate," "LDR," and "seed brachytherapy" in combination with words specifying individual sites, advantages, disadvantages, recent progress, advances, and usefulness.
Vendor product manuals were also retrieved.

Technical considerations
An ideal brachytherapy seed source should have a maximum isotropic dose distribution, relatively higher energy, lesser half-life, and a homogenous dose distribution. The source is encased in a metallic capsule for absorption of ß-particle emission. Different seeds have different dimensions, and a non-isotropic dose distribution.

3.2
Use of seeds across all sites: summary of clinical experience

Prostate cancer
The field of seed brachytherapy started nearly 100 years ago with its use in prostate cancer. Hundreds of thousands of patients have been treated with LDR brachytherapy (LDR-BT), with >15-years' follow up in major centers worldwide. In many institutions, LDR-BT is considered the gold standard for prostate brachytherapy in low-risk patients, and contributes to most of the experience of seed brachytherapy. 11 After the initial excitement following its use at the Memorial Hospital, subsequent adoption by several American urologists, and improvisations with Au-198 seeds, the approach fell out of favor, as prostate cancer was assumed to be relatively radioresistant. Furthermore, there were major radiation protection challenges with high energy of Au-198, and EBRT was fast gaining popularity due to its non-invasive nature. How-

Brain
The use of seed brachytherapy in the brain was pioneered by Mundinger in the early 1960s, initially with the use of Iridium-192 (Ir-192) wires, and later switching to I-125 seeds. 25,26 Temporary implants are preferred over permanent implants in benign or low-grade tumors due to the lower risk of brain edema. The I-125 seeds utilized in the brain have a low activity (<20 mCi), extremely low dose rate (5-20 cGy/h), and provide a dose of 50-60 Gy at the tumor margin for slow-growing tumors, such as low-grade gliomas. Generally, one to five seeds are used, and stereotactic frame-based methods are used under general anesthesia for 3-D planning. In initial studies, CT information was used for definition of the target volume, and later availability of MRI and biological imaging-based fusion techniques made definition of the target volume more refined. 27 Although this improved precision has improved local control, it has not yet shown a survival advantage. 28 The procedure is carried out under pre-and postoperative steroid cover. Temporary implants require another procedure for seed removal after 20-30 days under local anesthesia and without stereotactic equipment. 29 Special attention is required for high-dose areas (>150 Gy), which should lie within the tumor and away from blood vessels. Animal experiments have shown a breach of the bloodbrain barrier approximately 7 days after implantation, which lasts for almost 1 year, before restoration of near normal function at 2 years. 30 Evidence of its use at present is limited to retrospective uncontrolled trials and case series, and the general consensus is that the treatment should be reserved for highly selected patients. 7

Lung
Since the 1980s, I-125 brachytherapy has been used in the treatment of non-small cell lung cancer patients who are ineligible for curative surgery. 43  Furthermore, a randomized study that compared I-125 seeds with conventional radiotherapy in large (5-10 cm) unresectable stage 3-4 lung cancers showed a better overall response rate in the brachytherapy arm (88% vs. 59%), translating into significantly better 2-year survival (37.1% vs. 11.1%), as well as superior symptom control and QOL. 46 Interstitial procedures at different sites might be repeated multiple times for recurrent lung metastases with good efficacy and tolerance; 47 the procedure uses CT guidance with coplanar (3DPCT) or non-coplanar three-dimensional printed templates (3DPNCT).
Non-coplanar techniques may require fewer needles, as well as a reduced need for breaking/crossing ribs to achieve the desired dose distribution. 48

Pancreas
Several

Author, year of study n, site-indication Seeds [technique] (dose) Results Toxicity
Sneed et al. 35

Other sites
Seed implants have also been carried out in additional sites including the breast, liver, head and neck, mediastinum, and gastrointestinal tract, and the results are summarized in Table 2. 58-67

Radioactive seeds in reirradiation
Permanent seeds with LDR and VLDR properties are considered safe and popular for reirradiation of recurrent tumors. Common sites include gynecological malignancies, brain tumors, head and neck cancers, and prostate cancers. Findings from the majority of series are limited by heterogeneity, a long inclusion period, and highly selected cases.
Owing to their relative ease of use and tolerability, permanent seeds are a worthwhile option, even for patients with poor performance status. Furthermore, seed brachytherapy has shown promise in recur-

Complications and disadvantages of seed brachytherapy
In keeping with the maximum experience with seed brachytherapy in prostate cancer, problems such as seed dislodgement or migration have been most studied in prostate cancer. Reports have documented migration not only within the prostate, but also at distant sites, including the lung and coronary artery. Seed migration poses a significant hazard, and the maximum risk is found with seeds in loose form. Furthermore, local movement of seeds with the prostate might affect the sectoral dose, whereas dosimetry of the whole prostate might be unaffected. Clinical results have not yet been able to implicate these local migrations to a reduced possibility for cure. 72 Distant migration of seeds to lungs or other vital organs can cause temporary self-limiting side-effects, such as bloody sputum, pneumorrhagia, pneumothorax, and also late sequelae, including secondary cancers. 73,74 The use of seeds also carries the risk of radiation exposure to health workers; however, due to their low energy, ample protection is available. The procedure is operator-dependent, and variation between planned and actual seed positions can occur; preimplant dosimetry can guide but not guarantee conformity. Areas with more or less than the prescribed dose cannot be corrected after the implant, and as a result, permanent brachytherapy remains a less preferred option for both patients and hospitals.

Upcoming frontiers in seed brachytherapy
Several innovations are underway to overcome the current limitations of seeds. Results showed reduced migration with the use of stranded seeds, and reduced mobility potential from initial implant location with Vicryl coating are encouraging. 75,76 However, although stranded seeds experience less dislocation, they allow limited flexibility in optimizing the dose in critical areas; for example, in limiting the urethra dose in prostate cancer. Consequently, a combination of stranded and loose seeds might help to overcome their relative disadvantages. Furthermore, several companies are attempting to reduce the production cost of seeds by encouraging local manufacture. Preplanning procedures help to reduce the intraprocedure time, which as a result, reduce the radiation exposure to workers. Other new methods include the use of robots to further reduce radiation exposure, and applicators and techniques have already been developed for robotic controlled brachytherapy in the prostate and lungs. 77 Apart from the radiation safety aspect, robots might also add to the efficiency and skill of seed placement. 78 However, seed brachytherapy procedures for oral cancer cannot be carried out with robots, as the target region is at or close to the surface and critical organs; hence, the seeds needs to be implanted one-

DISCUSSION
LDR aims for dose rates of <200 cGy/h, which, over time, enhances the therapeutic ratio. The ongoing sublethal damage repair is more effective in normal tissue than in malignant tissues. Because of the disadvantages of LDR applications, including radiation exposure to personnel during source placement, efforts were made to devise sources with a short half-life, high specific activity, and low energy X-ray emitters; these improvements would enable a small amount of material to be placed in the tissue, which would lose its radioactivity soon after curing the disease.
The first Rn-222 seeds consisted of glass capsules, but were soon encapsulated by a gold envelope to prevent the release of harmful ßparticles. 82 For several years, permanent seeds remained the main- it might be appropriate to revert to basic radiotherapy, such as seed brachytherapy, to achieve comparable results to SBRT techniques and even proton therapy. 80,84 Although there is conflicting opinion on the cost-effectiveness of seed brachytherapy techniques compared with other sites and techniques, developing countries, such as Brazil and India, are attempting to overcome these issues by innovative techniques and local manufacture of seeds. 85,86

CONCLUSIONS
Technical advances in seed brachytherapy have lagged behind those in EBRT and HDR brachytherapy over the past few decades; however, there has been a renewed interest in seed brachytherapy due to its encouraging clinical results in primary settings, as well as their potential for use in reirradiation for recurrent disease across several sites.
However, there remain several limitations that need to be addressed with the innovation and application of new technologies.