Learning from the past: a century of accuracy, aspirations, and aspersions in brachytherapy

Abstract

The oldest form of radiation therapy, brachytherapy, has been investigated and reported in the scientific and medical literature for well over a century. Known by many names over the years, radium-based, empirical practices evolved over decades to contemporary practice. This includes treatment at various dose rates using multiple radionuclides or even electrically generated photon sources. Predictions or prognostications of what may happen in the future enjoy a history that spans centuries, e.g. those by Nostradamus in the 1500s. In this review article, publications from several eras of past practice between the early 1900s and the late 2010s where the authors address the “future of brachytherapy” are presented, and for many of these publications, one can use the benefit of the intervening years to comment on the accuracy or the inaccuracies inherent in those publications. Finally, recently published papers are reviewed to examine current expectations for the future practice of brachytherapy.

Introduction

In the annals of science, there have been many profound predictions or presumptions that were later definitively found to be true. A relatively recent example is the Higgs boson, an elementary particle first postulated in two seminal papers (published in 1964), that would subsequently mathematically support the contemporary understanding of the Standard Model of particle physics. ^1,2 It was not until 2012, that the Higgs boson was experimentally observed at the Conseil Européen pour la Recherche Nucléaire (CERN) in Geneva, Switzerland. ³ However, there are as many, if not more, examples of incorrect predictions and assumptions. In continuation of the theme of elementary particles, J.J. Thomson is credited with proposing the “plum pudding” model of atomic structure, later revised and improved upon by the famed scattering experiments of Earnest Rutherford in 1911, which in turn was supplanted by the invention of quantum mechanics. ⁴ The scientific method of research relies on rigorous testing of a well-stated hypothesis, but what if the implications of the hypothesis are unknowable, e.g. when attempting to predict the future?

Within a matter of years from their discovery, radiation and radioactivity revolutionized medicine with advances pertaining to both medical imaging and therapy. Brachytherapy is the oldest form of radiation therapy, having celebrated a century of use nearly 20 years ago. The evolution of brachytherapy from manually placed radioactive sources to image-guided, remote afterloading parallels over a century of scientific and technical advances. Throughout this time, several prominent, contemporary scientists and clinicians have attempted to predict the clinical practices and technical approaches that would become common in the future. Now, with the added benefit of hindsight, it is our goal to review a selection of these predictions regarding the practice of brachytherapy and evaluate how prescient or myopic they were, and in the cases of the latter, to try and appreciate why predictions went astray.

Methods and materials

The authors performed a literature search using keywords of “future” and “brachytherapy” and paired the results to find at least three representative publications predicting the ‘future of brachytherapy’ during four general time eras. These eras were: 1900s–1930s, 1940s–1960s, 1970s–2000s, and 2010s to the present. Additionally, the authors utilized publications and resources from their own personal collections, including those from educational programs, residency training, research, and personal interest. The basic requirement for inclusion was that the referenced publication include statements regarding the author’s assessment of future practices, expected developments, needed advances, or equivalent regarding the practice of brachytherapy. The goal was to appreciate the work that has taken place and to apply it to contemporary predictions of future practice.

Discussion

The advent of brachytherapy [1900s –1930s]

Writing to Dr Sowers from his vacation home in Baddeck, Nova Scotia, Alexander Graham Bell noted the ‘unsatisfactory’ process by which externally applied radiation from Roentgen’s X-rays or radium was that the radiation had to “pass through healthy tissues of various depths in order to reach the cancerous matter.” ⁵ Bell went on to posit “there is no reason why a tiny fragment of radium sealed up in a fine glass tube should not be inserted into the very heart of the cancer”, and with that statement, Bell was one of the first to suggest what would come to be known as interstitial brachytherapy. He also correctly anticipated the widespread use of radium in therapeutic medicine.

However, Bell incorrectly predicted the material utilized for encapsulation! Glass encapsulation was sparingly used for permanent implants over subsequent decades, largely due to the obvious risk of breakage. In the specific case of radium, an encapsulation material with high atomic number was essential for shielding patient tissues from energetic α and β particles. By the 1930s, radium sources were encapsulated in a platinum and iridium mixture of varying concentrations. Today, titanium is commonly used for a number of Low Dose Rate (LDR) and High Dose Rate (HDR) sources, although other encapsulations have been reported including plastic polymer, ⁶ bioabsorbable polymer, and resin, among others. Although glass has recently made a resurgence in the delivery of Y-90 microspheres.

Following the adoption and application of radium as a medical device, many practitioners began studying various radiation properties of the material. By 1921, a famous physicist named Edith Quimby had determined that radium, when used for surface molds, did not perfectly follow inverse square law (or “Newton’s inverse square law”, as it could be called). ⁷ Not only was this deviation from inverse square appreciated, but also the effect of oblique filtration through the source encapsulation or applied filters was described.

Next, she attempted to quantify an amount of biological response based on the amount of radiation which the tissue was exposed to. However, calculations at this time were hampered by a lack of an accepted dosage unit. After the adoption of the “γ roentgen”, she devised the first “look up” tables which evolved into “along and away tables” for linear sources in a semi-empirical dose calculation. ⁸ The process of source-dose quantification was also investigated in this time period by Sievert, ⁹ Paterson and Parker, ¹⁰ and Mayneord, ¹¹ among others. While these tables were useful for points directly under the applicator, they required a massive amount of hand calculations for each source and position combination. Quimby noted “If it were possible to find such an expression for the intensity under different parts of a tube, it would simplify the accumulation of further data of the sort presented.” ¹² She correctly predicted the concepts that ultimately evolved into the principles used in modern day treatment planning and the AAPM Task Group 43 (hereafter, TG-43) report algorithm. ¹³

Claude Regnaud, one of the first practicing French physicians at the Curie Institute, provided a review of three decades of radium use at a 1929 lecture to the West London Medico-Chirurgical Society and closed with a listing of key limitations in the practice of radium-therapy. ¹⁴ The first was that “all procedures of attacking cancers have been tried.” The procedures summarized included radium-surgery, “focal Curietherapy” (classical brachytherapy), plastic molds for surface plaques, telecuritherapy (known then as radium “bombs”), and “general Curietherapy”—where radium was dissolved into the bloodstream with the hope it would concentrate in tissue requiring treatment. Ultimately, Regnaud called general Curietherapy a “fanciful hypothesis;” however, we now know modern radiopharmaceutical and immunotherapy interventions are efficacious options for the treatment of many primary and metastatic diseases. ¹⁵ Of course, Regnaud could not anticipate the decades of development, delivery systems, and treatment modalities that would follow this lecture. The second item was to acknowledge the “narrowness of the margin between radio-sensitivities of normal and neoplastic tissue.” With this comment, we can appreciate how much these early providers had already learned about radiobiology and were pioneering analogs of modern-day normal tissue complication probability curves. Regnaud proposes both investigating mechanisms to modify the biological response of tumors and exploiting the “time factor” that differentiates tumor response from normal tissue. Regarding the latter observation, he noted that exploiting this advantage could “allow progress relative to other types of cancer,” a comment foreshadowing development of varying fractionation-dose schedules. The third and final limitation regarding radium therapy was that there was a limit to the size of tumors that could be treated. Thus, Regnaud concluded that contemporaneous techniques could not “equalize the distribution of a dose of rays in a very large volume” or the risk of “irremediable damage to organs indispensable to life”, such as in the neck, thorax, and abdomen, would ultimately limit the general applicability of radium. For some time, this was true; it was not until the 1950’s where implant systems would ultimately allow for relatively homogeneous dose distributions and safe, efficacious treatment of larger volumes.

Dawn of the nuclear age [1940s–1960s]

Following the publication of standardized tables and systems, a need emerged to methodically describe the anticipated radiation effect of an application. In 1952, Quimby and Castro presented an update of their techniques for optimizing both the Patterson-Parker and the Quimby-based systems. ¹⁶ They extended the traditional Patterson and Parker system into larger geometries and found that it generally performed very well; however, a concern arose that the overall amount of radium implanted may result in substantially higher dose rates. Clinicians, noting treatment morbidity from higher concentrations of radium (e.g. 5 mg/cm rather than 1 mg/cm), extrapolated those radiobiological effects as a function of dose rate. Thus, they recommend decreasing the overall dose rate, while admitting that there are no clinical data to support the decision. The challenge was that there were few options available to clinicians, and geographical differences in source strength per unit distance were variable between different regions! As larger quantities of radium became available and the field later shifted to Cs-137, there were multiple source strengths available, mitigating this concern. ¹⁷

In 1963, Laughlin and colleagues summarized the state-of-the art in brachytherapy dosimetry. ¹⁸ While the authors didn’t explicitly hypothesize future patterns of care, in their introductory paragraphs they note the importance of being able to not only generate a three-dimensional dose distribution, but also to do so quickly, saying “this comprehensive dose analysis should be available in a reasonably short period of time.” Both items are now considered hallmarks of modern brachytherapy dosimetry, with an extreme example being GPU accelerated bi-objective treatment planning for modern image-guided prostate brachytherapy. ¹⁹ One notable difference, however, is that Laughlin et al describe that the dose calculation should consider inhomogeneous tissue composition “to the extent it is known.” In the text of the publication, the authors note the differences between attenuation in air compared to tissue, but the concept of heterogeneity-corrected brachytherapy treatment planning is one that would be of interest to the field for another 60 years and would come to significant prominence in the 2000s and 2010s.

In 1969, Frank Attix published the first edition of Radiation Dosimetry, a seminal publication on all aspects of dose determination. The 31st chapter “Dosimetry in Implant Therapy” was authored by Robert Shalek and Marilyn Stovall and provides a comprehensive review of brachytherapy dosimetry at that time, during which computer-based calculations were just becoming available. Notably, they reported the existence of 11 computer methods between 1958 and 1966. ²⁰ The authors close the chapter with a list of anticipated developments in interstitial and intracavitary techniques. The first advance is remote afterloading, where they note that outpatient treatment of carcinoma of the cervix was already achieved in minutes compared to prior multiday implants with associated reduction in staff dose. The remaining contemporary challenge for these techniques, now known as high-dose rate brachytherapy, was to understand the optimal dose and fractionation schemes for this new modality. At the time, there was little clinical data and limited understanding of radiobiology. To a large extent, radiobiological modeling remains an area of active discussion half a century later.

An additional anticipated development was the use of “low-energy” radionuclides; however, to Shalek and Stovall low-energy sources were Rn-226 (radon gas) and Au-198 with average energies of 0.83 and 0.41 MeV, respectively. Further challenges for those sources were their high cost, incomplete dosimetry data, and unknown radiobiological response. Today, low energy is generally considered to be <0.05 MeV where the photoelectric effect is dominant. Low-energy sources containing I-125, Pd-103, or Cs-131 are more affordable, have consensus dosimetry data, have been used in clinical trials, and have radionuclide-specific prescriptive guidance from professional societies. ^21,22

The final anticipated development reported was the use of computer calculations. They noted benefits “if calculations can be performed before treatment begins,” as well as the benefits of varying source strengths to generate a patient-specific plan, both of which can be accommodated into modern workflows. In both modern day HDR and LDR, the anticipated treatment plan is calculated prior to treatment and either the source strength specifically chosen (in the case of LDR) or effectively modulated (in the case of HDR) with the modification of dwell times.

Rise of remote afterloading technology [1970s–2000s]

A 1983 speech to the European Society for Therapeutic Radiology and Oncology by Bernard Pierquin provides a robust overview of 80 years of clinical experience along with thoughts on the future. He commented “Finally, it is the computer that remains the master of the game of modern endocavitary brachytherapy.” ²³ That statement, while true, was limited in that the computer would come to be the master of nearly the entire practice of brachytherapy, not just in the adaptation of Ra-based therapies to Cs-137 and/or Ir-192. Regarding a vision for the future of brachytherapy, Pierquin stated that “Interstitial and plesiobrachytherapy are indicated for all tumor locations that are easily accessible to direct instrumentation, the locoregional extension of which remains minimal or moderate” and endorses brachytherapy techniques as primary or boost treatment to a wide variety of anatomic sites. He even noted potential applications in palliative radiation therapy, while noting it was primarily being used in Phase I research studies. However, Pierquin’s vision of the widespread employment of brachytherapy has not come to pass as brachytherapy has instead seen a decrease in utilization in the modern era, particularly in the United States. ^24–26

In a 1988 book edited by Mould for a Selectron users meeting, Joslin authored a chapter on ‘The Future of Brachytherapy.’ Joslin noted the advances in brachytherapy since the 1950s, including the use of afterloading techniques, the introduction of new source radionuclides, the advent of high-activity miniaturized sources, and the growing role of automation and computer control. ²⁷ At this time, remote afterloading was in its third decade of use, and Joslin listed a number of important characteristics that needed to be addressed to help identify a role for brachytherapy in cancer treatment. These characteristics are listed here in their entirety:

• “A universal system of source measurement and calibration.

• A universal system for dose specification and reporting.

• Within any clinical trials programme provide a system of intercomparison of calibration dosimetry between centeres.

• Standardise nomenclature related to brachytherapy.

• Within any collaborative study attempt to standardise the technique used.

• Develop suitable morbidity scoring systems applicable for brachytherapy techniques.

• Establish appropriate clinical trials for those situations where they are both needed and feasible.”

This list of needs can be broken out into several basic aims: standardization of clinical dosimetry, standardization of delivery techniques and naming conventions, and guidance for physicians. Some 30 years later, there is still not a national standard for HDR Ir-192 calibration in the United States. While accredited calibration laboratories can provide source calibrations for clinicians, these systems cannot be traced to a primary standard! In contrast, the United Kingdom Institute of Physics and Engineering in Medicine (IPEM) established a primary reference air–kerma rate standard for HDR ¹⁹²Ir brachytherapy sources in 2004. ²⁸ In addition, the adoption of the TG-43 dosimetry algorithm ¹³ and expansion to high-energy sources ²⁹ allows for a robust, consistent, commercially available system for brachytherapy dosimetry. There have also been a number of professional society reports to guide and inform treatment in specific anatomic areas or with specific techniques; however, there have been few prospective, randomized clinical trials featuring brachytherapy (see section ‘The known future’ below). There is currently work being performed with the American Association of Physicists in Medicine to address the use of standardized nomenclature in the realm of brachytherapy in the upcoming update of TG-263. ³⁰

The 1970s and 80s was marked by development and adoption of new radionuclides that presented exciting opportunities for brachytherapy and were ultimately permanently adopted such as Co-60 and Ir-192. At the same time, there were many examples of promising new sources that would not find widespread use. Regarding the neutron-emitting Cf-252 source, Greening commented, “We will shortly find Cf-252 being used for <brachytherapy> purposes with its mixed γ and neutron radiation, and with the hope of radiobiological advantage from the neutron component.” ³¹ However, only a handful of clinical sites ultimately seriously considered Cf-252 brachytherapy, which like radium in the early days, was only available in very limited quantities, was difficult to shield, and was expensive to produce and chemically separate. In 1986, Ralph Fairchild filed a patent for the use of Sm-145 as a radiation (and brachytherapy) source. He stated, “while Samarium sources have been designed primarily for implantation in a brain tumor, they should be used for almost any conventional brachytherapy application.” ³² While samarium-153 was theorized and came to be used in the treatment of bone metastasis, ³³ the authors could not find a single publication regarding Sm-145 being used clinically.

In 1995, Gupta suggested four new sources to add to the armamentarium: Pd-103 as a way to improve implant radiobiology due to a shorter half-life, Sm-145 which is a “bone seeker” and could be used with iodinated drugs, Am-241 with a long half-life (>400 years) as a temporary implant, and Yb-169 with a low energy and half-life that could be used for both temporary and permanent implants. ³⁴ Gupta suggested that Yb-169 might replace Ir-192, I-125, and Pd-103 in the future and was first implanted at London’s Regional Cancer in 1990 (in Ontario, CAN). Meigooni and Nath also agreed with these radionuclides having value and did an extensive study into their radial dose functions. ³⁵ Virtually all these proposed radionuclides, with the exception of Pd-103, were ultimately disappointments. Am-241, similar to Sm-145 discussed above, was essentially never used clinically. While Yb-169 has not been widely adopted as a brachytherapy source, it may be increasingly used in the production of Lu-177 via the indirect production route ³⁶ and new projections are being made with its use as an HDR source. ³⁷

A 1997 review by Nickers and colleagues discussed the current state and future prospects of brachytherapy. ³⁸ The field had shifted from Ra-based practice to Cs-137 and Ir-192. Furthermore, permanent implants with low-dose rate I-125 sources were beginning. The authors noted several limitations in the “classical’ practices of brachytherapy, namely that there were few randomized clinical trials; challenges in treating deep-seated tumors and areas with complex anatomy; and that the costs of hospitalizations associated with inpatient procedures made brachytherapy less cost-effective compared to external beam. Nearly a quarter century later, these same challenges remain! In a summary of new techniques, the authors included ultrasound-guided implants (breast or prostate), endobronchial intraoperative HDR, new radionuclides (including Pd-103 and Yb-169), pulsed dose rate (PDR) afterloading, and finally, the use of plastic catheters for interstitial treatment with hyperthermia probes or an HDR source. In this short list, the authors touched on a few items that would evolve to become mainstream and a handful that did not. Ultrasound-guided prostate brachytherapy (HDR & LDR) is now quite common; however, it may be more accurate to note that volume image-based brachytherapy treatments have become standard-of-care. Plastic catheters and implants are now widely available from multiple vendors. Finally, while the use of hyperthermia in conjunction with brachytherapy has waxed and waned over the decades, it has not fully disappeared from research and development. ^39,40

Modern era [2010s–present]

The Medical Physics journal invited Vision 20/20 articles to postulate and predict the future. In this section, we review three recent Vision 20/20 articles as applied to brachytherapy.

Dose calculations for brachytherapy were standardized with the publication of the American Association of Physicists in Medicine Task Group 43 report ¹³ and subsequent update. ⁴¹ The formalism was configured to not only standardize dose calculation algorithms to improve accuracy, but also to permit interinstitutional comparison of patient outcomes. The formalism accomplishes these goals through a modular approach that relies on an assumption of an infinite homogeneous water geometry. Limitations of the formalism were thoroughly invested throughout the 90s and include the inability to account for tissue and applicator heterogeneities as well as finite patient dimensions. Although Monte Carlo radiation transport codes have long been an alternative, their prohibitively long calculation times have prevented clinical implementation. Considerable attention in the literature was given to model-based dose calculation algorithms (MBDCAs) in the years surrounding 2010. ⁴² These algorithms utilize a deterministic, rather than stochastic approach, to solve the linear Boltzmann transport equations and achieve the efficiency of TG-43, but with the accuracy of Monte Carlo codes. Rivard et al published a Vision 20/20 manuscript identifying the challenges of implementing MBDCAs into clinical practice, including the development of new quality assurance standards for treatment planning systems and dose specification considerations including through which medium radiation should be transported and dose deposition be calculated. ⁴³ The AAPM published Task Group 186 only 2 years later to provide physicists with recommendations for integrating MBDCA’s into clinical practice. ⁴⁴ With another decade having passed, much work remains to address the salient points of Rivard et al and the Task Group 186 members before widespread implementation can occur of these more advanced treatment planning algorithms. In a survey of medical physics residency program directors conducted by the Unit 72 of the AAPM, only 15% of programs indicated they had adopted MBDCAs in their clinic. ⁴⁵

In Rivard’s Vision 20/20 papers, the authors postulated additional treatment planning-related predictions, some of which have become a clinical reality and others are still waiting in the queue. The transition of implant equipment, including applicators, toward MRI-compatibility has occurred as well as the development and implementation of hybrid applicators that combine the concepts of intracavitary and interstitial implants. Physicists continue to wait for dual-modality dose summation within commercial treatment planning systems along with the ability to incorporate radiation biology into dose distribution calculations. Finally, the long-anticipated absorbed dose to water standards for both HDR and LDR brachytherapy sources remain elusive.

In-vivo dosimetry (IVD) has been a standard for dose verification of external beam radiotherapy for years. ^46,47 Since brachytherapy fraction doses are often large [>5 Gy] and many steps in the treatment processes are achieved manually, routine dose verification would improve patient safety and confidence in dose delivery. ⁴⁸ With the onset of standardization of 3D data set acquisition and planning within brachytherapy, it was hypothesized in a Vision 20/20 article that in-vivo dosimetry could also become the standard of care for brachytherapy treatments. ⁴⁹ As described in the article, in-vivo dosimetry measurements are particularly challenging in this realm because of high dose gradients, difficulty in detector positioning, temperature and energy dependence of detectors, and poor sensitivity. Challenges beyond the dosimeters themselves include patient discomfort and added workload to clinical staff. Hence, current research is moving away from point-based integrating dosimeters. Recently, source tracking technology may be the most promising endeavor, though this is still not performed at very many centers. Unfortunately, the use of routine implementations of IVD for error detection is still “yet to come,” ⁵⁰ although, as described in a recent review article there are groups working on addressing barriers to clinical implementation. ⁵¹ In vivo dosimetry is yet the focus of some research and clinical studies. ^52,53

The known future

As discussed above, the need for clinical trials to advance and refine the practice of brachytherapy was articulated by some, including Joslin in 1983. While there have been few prospective clinical trials utilizing brachytherapy, those that have been performed have had a notable impact on clinical practice and changed practice patterns. While not a traditional prediction of the future, the hypothesis underlying a proposed clinical trial may become the practice of the future, pending the results of the trial.

The Collaborative Ocular Melanoma Study (COMS) was initiated to evaluate two different end points. While one arm evaluated the use of external beam lor large melanomas in the pre-operative setting, another arm of the trial evaluated the use of brachytherapy as an alternative to surgical intervention, namely enucleation, for medium-sized tumors. ⁵⁴ Brachytherapy offered patients an eye-sparing option for tumors between 2.5 and 10 mm in apical height with basal diameters less than 16 mm. This arm enrolled a total of 1317 patients between 1986 and 2003 and included 5–15 years of follow-up. Report 28 included patients with a minimum of 12 years of follow-up and confirmed the finding that patients receiving plaque brachytherapy experienced equivalent survival rates to those undergoing enucleation, a significant surgery including removal of the affected eye. While relatively rare, ocular melanomas are now commonly treated with brachytherapy—largely as a result of COMS trial, and societal guidance is available to inform and guide clinicians. For larger tumors or for proximity to the optic disk, other radiation therapy techniques may be considered (e.g. proton therapy or stereotactic radiosurgery); however, the COMS normalized brachytherapy in this setting.

In contrast to the COMS study that expanded the role of brachytherapy, the American College of Surgeons Oncology Group (ACOSOG) sponsored the Z4032 trial to evaluate the role of brachytherapy following sublobar resection of lung tumors. ⁵⁵ This study randomized 224 patients to either a sublobar resection or sublobar resection with permanent LDR brachytherapy treatment administered to the tumor bed. The primary end point was the local recurrence rate at 3 years, and the study ultimately showed that there was no improvement in local recurrence with the addition of brachytherapy resection. Of note, the parenchymal margin status was used as a subset analysis, but the study wasn’t powered to evaluate that end point, although local recurrence trends favored brachytherapy in the setting of inadequate (<1 cm) surgical margins. This result notably reduced the use of brachytherapy in this setting, and contemporaneous trials designed to compare stereotactic lung radiotherapy to sublobar resection with brachytherapy ⁵⁶ were eventually abandoned and closed to accrual.

For gynecological cancers, patterns of care have shown a decreasing utilization of brachytherapy and increasing reliance on external beam in the United States; however, brachytherapy was also associated with better outcomes with regard to cause-specific survival and overall survival. ⁵⁷ Fortunately, other multicenter efforts have worked to refine and improve the use of brachytherapy of the cervix. Namely, the EMBRACE I and RetroEMBRACE demonstrated that clinical outcome is related to brachytherapy technique and dose. The subsequent study, EMBRACE II, is designed to standardize image-guided brachytherapy along with other treatment techniques in the modern setting. ⁵⁸ The early EMBRACE studies normalized and standardized the use of MRI-based image-guided brachytherapy, including adaptive treatment techniques. EMBRACE II is designed as a prospective study continuing these efforts and is the culmination of over two decades of work towards improving patient outcomes with highly patient-focused treatment

The unknown future!

Crystal gazing for predicting the future of the field of brachytherapy has produced mixed results as evidenced by the previous sections. Recently (within the past 3 years), there have been several publications that attempt to postulate future advances and directions for brachytherapy as a treatment modality. ^59–64 The following pertinent major themes were noted amongst these publications:

i. Machine learning and artificial intelligence:

The impending takeover of machine learning and artificial intelligence (AI) in various fields of medicine has been promised for a while. Regarding brachytherapy, the prediction of Cunha et al is that deep-learning-based workflows for image processing, including segmentation and device digitization, as well as automated intelligent treatment planning have substantial future potential. Deep learning will profoundly impact the field of brachytherapy with advances in image processing (specifically, image enhancement, registration, segmentation, applicator reconstruction, and seed identification) and treatment planning according to Song et al. The authors also state: “We think DL <deep learning> may play a critical role by supplementing clinical practice with virtual human expertise.” Fianda et al express that AI can help in the establishment of decision supporting systems pertaining to the areas of automating repetitive tasks, optimizing time, modeling patient and physician behavior in “heterogeneous contexts”, amongst others. The authors also postulate implementation of AI in the clinical workflow will facilitate patient consultation, target volume delineation, treatment planning and delivery resulting in improvement of both clinical outcomes and quality assurance. Banerjee et al state that brachytherapy is currently highly physician skill and technique dependent, and AI will aid in establishing uniformity in brachytherapy practice across the world once standardized AI models are generated. ⁶⁵ The authors believe AI “is likely to improve process efficiency, consistency and quality” but also state that human intervention and quality checks will be essential for a while.

ii. Direction and/or intensity modulated brachytherapy:

Conventional brachytherapy techniques usually rely on azimuthally symmetric sources for dose delivery. Cunha et al predict that the intensity modulated brachytherapy (IMBT) technique, which includes use of intracavitary mold applicators with shielding as well as dynamic modulated brachytherapy, will aid in improving treatments for rectal cancer and that a rotating shield brachytherapy approach for cervical cancer is also promising. The study also proposes that direction modulated brachytherapy will improve breast and prostate cancer brachytherapy treatments. According to Song et al, IMBT is a promising technique and current technological developments such as direction-modulated brachytherapy applicators, ^66,67 rotating shield brachytherapy, ⁶⁸ CivaSheet^®, ⁶⁹ static IMBT ⁷⁰ and dynamic IMBT, ⁷¹ will translate as advancements into current clinical practice for brachytherapy treatments involving gynecological, prostate, rectum, breast, and ocular sites. While these manuscripts share a favorable outlook towards intensity modulation of a brachytherapy source, the technique has been discussed for multiple decades and has not been implemented into any commercially available delivery systems. In contrast, static anisotropic sources have recently become commercially available. Also, in addition to new direction and/or IMBT sources and techniques, a novel brachytherapy source called diffusing alpha-emitter radiation therapy (DaRT) seed has been recently developed and is currently under research and development phase. ⁷²

iii. Three-dimensional (3D) printing, and phantoms:

In-house 3D printing has gained traction over the last decade in radiotherapy clinics. 3D printing is predicted to revolutionize brachytherapy as adoption of customizable applicators will enable personalized dose delivery and reduce the importance of physical skill. ⁵⁹ It is postulated additive manufacturing (i.e. 3D printing) will be a catalyst for “increase of spatial or dosimetric accuracy, increased flexibility with regard to catheter or needle trajectories, improvement of workflow, reduction of cost, or improvement of the patient experience.” ⁶³ Cunha et al also predict electromagnetic tracking would help automate aspects of quality assurance and applicator reconstruction. It was also expressed that further development and improvement in phantoms for quality assurance and control are required to keep pace with brachytherapy-related clinical advancements. ⁶⁴ In addition, the authors posit rapid prototyping (i.e. 3D printing) along with tissue mimicking material development will help in organ modeling and improve brachytherapy-related dosimetric measurements.

iv. Functional imaging and radioimmunotherapy:

The integration of functional imaging into brachytherapy treatments may potentially improve treatment practices and outcomes. “There are extraordinary future possibilities for functional imaging techniques to guide brachytherapy at all stages of patient management. These present and future innovations may hopefully ultimately lead to higher cure rates and less treatment-associated toxicity” according to Lucia et al. Functional imaging, the authors predict, will enable better initial staging of disease, use of biomarkers for treatment response, precision in target definition, dose painting, and better patient selection. Cunha et al postulates use of biomarkers (molecular and imaging) and biology-based dose planning (biological optimization) are areas of future advancements. It is the opinion of Fleischmann et al, that radiotherapy and immunotherapy have a synergistic effect based on observed enhancement of local and systemic immune response. The authors state: “…brachytherapy could be an underestimated partner with immuno-therapeutic approaches in both curative and palliative settings, to generate local and systemic response.” Brachytherapy in conjunction with immunotherapy, the authors forecast, can potentially improve treatment outcomes for uterine cervical cancer, head and neck squamous cell carcinoma, skin cancer, triple-negative breast cancer, amongst others based on checkpoint inhibitors. In the future, it is hypothesized, adaptive T cell therapy and immune modulators (cytokines, cancer vaccines, and oncolytic vaccines) in combination with brachytherapy will provide a vast number of opportunities and challenges. These forecasts agree with the current growth and emphasis on genome-based medicine.

Where is the oldest radiotherapy modality headed in the near future? That question remains to be answered. A study by Miljanic et al might provide some insight in terms of innovation. ⁷³ An analysis of patent innovation in the field of brachytherapy for the preceding two decades was presented in this publication. The study reported an increase in patent productivity and brachytherapy innovation (129–202) from 2009 to 2018 when compared to 1999 to 2008, with an increase in academic participation (4%–11%), and a decrease in industry affiliation (83%–76%). The overall focus of inventions also evolved in these time periods. Innovations based on radiation sources (30.2%) treatment delivery (29.5%), body insert/catheter (9.3%), radiation dosing (8.5%), and imaging (6.2%) were dominant from 1999 to 2008, while treatment delivery (19.3%), exogenous agents (15.8%), radiation sources (9.4%), microparticles (6.9%), and treatment planning (5.9%) were prevalent from 2009 to 2018. The recent focus of brachytherapy-related patents based on exogenous agents (drug-conjugates, radiosensitizers, and adjuncts) and microparticles is notable.

Finally, will the utilization of brachytherapy keep on declining ^23,74–77 based on treatment caseload or have a renaissance ⁷⁸ remains to be seen.

Conclusions

“I never think of the future, it comes soon enough.” With this wise quote from Albert Einstein, we are reminded that our thoughts on the past, present, and future are all populated by our perspective on the events that shape the world. Predicting the future paths of science and technology is difficult as the future is elusive. Often what we think will happen does not, and that which will not becomes a black swan. ⁷⁹ Additionally, people tend to support and discuss their own interests and biases as the authors of this paper also found in determining what events and milestones to present. What is universally true is that the present is exciting, interesting, and above all, valuable.