A Message From the President
Welcome to the February issue of the brachytherapy blast.  I hope many of you have been able to participate in the newest virtual content produced by the ABS. I, for one, greatly enjoyed the GYN school which was held this past week and hosted by Drs. Gita Suneja, Akila Viswanathan, and Beth Erickson. The meeting enrolled nearly 150 radiation oncologists and physicists who participated in this highly interactive meeting. The plans are coming together for our annual meeting which will be in Denver from June 15th to the 17th. The meeting will involve highlights of brachytherapy research, practical sessions on implementing innovations in brachytherapy, and even a Shark Tank-style event to hear about what our colleagues think the future holds in brachytherapy.

One vision for the future of brachytherapy is included in this month’s brachytherapy blast. Dr. Chris Deuful reviews a prototype US-guided prostate HDR system with electromagnetic tracking which could allow a treatment plan to be generated in real-time. These approaches can bridge the gap that can be experienced with current approaches where the actual delivered dose differs from the planned dose.

Dr, Agarwal, and colleagues review the evidence for brachytherapy boost or an SBRT boost approach. With emerging trials shedding light on the differences between these approaches it is clear that a BT-boost for offers significant benefit without an increase in toxicity.

In honor of black history month, Dr. Mitch Kamrava discusses the remarkable career of Dr. Charles Mansfield, ASTRO gold medalist, and pioneer in the development of breast brachytherapy. 

We hope you enjoy this issue of the BrachyBlast. I hope many of you are making plans to attend the Annual Meeting in June!


Ann Klopp, MD, Ph.D.
President, ABS

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Dose Escalation for High-Risk Prostate Cancer: Brachytherapy versus Stereotactic Body Radiotherapy Boost
Manuj Agarwal, Christopher Wright, Shweta Manjunath, Arun Goel
 Department of Radiation Oncology, Perelman Center for Advanced Medicine,
University of Pennsylvania
The Increasing burden of high-risk disease and the rationale for intensification of local therapy
High risk (HR) prostate cancer (PCa) includes patients with ≥cT3a disease, Gleason 8-10, or PSA >20ng/ml. There has been an increasing proportion of men diagnosed with HR disease (1). The initial local therapy is most often between radical prostatectomy and radiotherapy. External beam radiation therapy (EBRT) with androgen deprivation therapy (ADT) is commonly used in definitive management. Dose-escalated (DE)-EBRT in the intensity-modulated radiation therapy (IMRT) results in a biochemical relapse of 22-45% of men at 8-10 years (2–5). Alternative means of dose escalation (DE) may appropriately intensify local therapy, resulting in improved biochemical control (BC) and subsequent downstream endpoints. Here, we review the roles of brachytherapy (BT) and stereotactic body radiation therapy (SBRT) as “boost” methods to escalate dose in the definitive treatment of HR-PCa. 

Brachytherapy Boost Review
There have been three randomized trials and a subsequent meta-analysis that supports the use of BT-Boost. ASCENDE-RT was a phase III trial comparing modern DE-EBRT to EBRT + LDR BT-Boost (6). All men received 12 months of ADT. After a median follow-up of 6.5 years, BC at 9 years was 83% in the BT-Boost arm versus 63% in the DE-EBRT arm (log-rank P<.001). Hypofractionated EBRT was utilized in the trial by Hoskin et al. comparing DE–EBRT (55 Gy in 20 fractions) + ADT versus EBRT + HDR BT-boost + ADT (7). Consistent with the findings of ASCENDE-RT, relapse-free survival was improved in the BT-Boost arm, with a median time to relapse of 116 months compared to 74 months for EBRT alone. Lastly, a randomized trial conducted by Sathya et al. showed improved BC for BT-Boost compared with EBRT alone (HR 0.53, 95% CI 0.31-0.88). These trials were not powered to demonstrate a significant difference in survival endpoints. Large database studies have demonstrated both prostate-cancer-specific mortality (PCSM) and overall survival (OS) improvements (8,9).

A National Cancer Database (NCDB) analysis of 44,833 HR-PCa patients from 2004 to 2013 showed improvements in (OS) with BT-Boost compared with DE-EBRT alone (10), even after adjusting for imbalances in prognostic factors, comorbidities, socioeconomic factors, and radiation dose (11). Similarly, Kishan et al. conducted a retrospective study of 1800 patients with grade group 5 disease treated at 12 tertiary care centers. PCSM and time to distant metastasis (DM) were improved with BT-Boost compared with DE-EBRT + ADT or radical prostatectomy (RP) (12). Taken together, these data underscore the importance of intensifying local therapy for HR disease.

Improvements in disease control may come at the cost of increased genitourinary (GU) and GI toxicity. In ASCENDE-RT, the cumulative incidence of late grade 3 GU toxicity was 18% and 5% in the EBRT + LDR BT-Boost versus DE-EBRT groups, respectively (6). These largely comprised strictures which were managed to result in a prevalence of 8 vs 2%. With improvements in technique and quality assurance, the same group has reported a 3% rate of late grade 3 GU toxicity (13). The use of HDR may be associated with a more favorable toxicity profile. In the aforementioned Hoskin et al. trial, there was no difference in acute or late toxicities between the DE-EBRT and HDR BT-Boost arms (7). A multi-institutional trial conducted by NRG Oncology (RTOG 0321) reported a 10-year rate of late GI and GU toxicity of 5% following EBRT (45 Gy in 25 fractions) and HDR BT-Boost (one HDR implant delivering 19 Gy in 2 fractions) (14). Corroborating retrospective studies of HDR BT-Boost showed similar low rates of GU and GI toxicities, with acute and late grade >2 toxicities of <5% and <7%, respectively (15,16). 

SBRT Boost Review
SBRT boost represents an alternative, non-invasive method for DE in HR-PCa. Retrospective experience is represented by five reports. Four reports utilized 6-7 Gy x 3, while 9.5-10.5 Gy x 2 was used in one (17–21). Two studies reported BCFS outcomes for high-risk patients at three years of 78 and 90% (19,20), and three studies reported five-year BCFS ranging from 69-90% (17–19). Toxicity outcomes were favorable, with only two trials reporting late grade 3 GU toxicities (2.5 and 6%) (19,20). These studies include relatively small numbers of subjects (41-108 patients), limited follow-up (33-54 months), a wide range of HR-PCa inclusion (24-100%), and heterogeneity in ADT utilization.

Two prospective experiences of SBRT boost combined with fractionated EBRT have been published, both with 24 months of follow-up. 36 men were enrolled in BOOSTER, a phase I sequential DE trial. 23/36 was high risk and 22/36 received ADT (22). 21/36 subjects ultimately received a 12 Gy x 2 boost (with the GTV receiving 15 Gy x 2). 3-year FFBR was 93.3%, acute grade 2 and 3 GU toxicity was 8% and 16%, respectively, and the cumulative incidence of late grade ³2 GU and GI toxicity was 14% and 0%, respectively. PROMETHEUS was a phase II trial that used a two fraction SBRT boost of 9.5-10 Gy (23). 24% of patients were high risk, and 54% received ADT. MRI fusion-based planning, intrafraction image guidance, and rectal displacement were mandated. The 2-year FFBR was 98.6%. Acute grade 2 GI and GU toxicity was observed at 4.4% and 26.6%, respectively with no grade 3 events. Late grade 3 GI and GU toxicity were low at 2% and 2.2%, respectively.

SATURN was a phase 1 / 2 prospective trial that investigated the simultaneous treatment of the elective pelvic lymph nodes with 5 fraction regimens in 30 patients (24). 25 Gy was delivered to the pelvis and seminal vesicles and 40 Gy to the prostate CTV, along with ADT for 12-18 months. Grade 2 GU acute and late toxicities were 46.7 and 52% respectively, and grade 2 acute and late GI toxicity were 3.3 and 32%. There were no reported grade 3 toxicities.

Pros/cons
There remains significant equipoise among North American GU radiation oncologists regarding the role of BT-Boost for HR-PCa (25). Compared to BT-boost, SBRT-boost has fewer retrospective data and shorter follow-up from prospective trials. A prospective randomized comparison between BT-boost and SBRT-boost can provide conclusions about their relative efficacy.

A propensity-score matched analysis compared patients receiving HDR or SBRT boost (26). The HDR group contained more HR patients (77% vs 62%), and fewer men received >18 months of ADT (35% vs 60.5%). At 5 and 10 years, there were no differences in BC or DM in the overall cohort or on subgroup analyses of HR disease, clinicopathologic features or ADT duration. Grade 3+ toxicity outcomes were similar, with 4.5 vs 3.0% urinary and 1.5 vs 0% gastrointestinal. Notably, the one patient with a grade 4 toxicity had received SBRT and developed a colovesicular fistula requiring colectomy.

Patient selection is critical when choosing the appropriate boost modality. SBRT boost and loose-seed LDR boost may be suboptimal in patients with seminal vesical invasion (SVI) when compared to HDR boost or LDR boost using a stranded or hybrid approach given the mobility of seminal vesicles (27). For patients who are not eligible or borderline candidates for BT boost (non-operable, large TURP defects, large prostatic volume, or significant urinary functional symptoms), SBRT boost may be an option.

Conclusion
BT-boost for HR PCa offers significant BC benefit, and when performed with modern technique, is not associated with an increase in toxicity. SBRT-boost offers a potential alternative, especially for patients ineligible for BT-boost. Further prospective data is warranted.

Can Tracking Technology Revolutionize How
We Execute HDR Brachytherapy
Christopher Deufel, Ph.D.
Mayo Clinic
For as long as I can remember, the HDR brachytherapy workflow has been associated with an ‘aha moment’ when the team discovers whether the implant yielded adequate dosimetry, whether too many or too few applicators were used, or whether the applicator position was optimum. In this regard, the standard way of doing HDR brachytherapy is backward because the desired dosimetry should inform the implant geometry and not the other way around. The standard HDR workflow also has a negative impact on the quality of our treatments. The treatment team is usually faced with a choice of extending the procedure by a significant amount of time to adjust the implant, re-image, re-digitize, re-contour, and re-optimize, or the team can accept an inferior plan and hope for a better result for the next fraction.

Our treatments would be of higher quality and implants would be faster if we could take away the uncertainty that leads to excessive applicator position adjustments or the use of more interstitial applicators than are necessary. For example, consider a system where you could place needles under CT, MRI, or Ultrasound (US) guidance with ‘target locations’ mapped onto the image along with isodose lines and DVHs that update in real-time once the applicator has been implanted. With this system, you know instantly whether the applicator needs adjustment using the live display of the isodose lines and DVH metrics, and the plan is immediately ready for approval when you finish placing all applicators. This type of system would eliminate the aforementioned ‘aha moment’.

A crucial piece of technology has been necessary to realize this vision, namely instantaneous and automated applicator digitization during the brachytherapy implant. Recently, tracking technology has been evaluated by researchers for monitoring the position of a brachytherapy applicator in real-time. Tracking technology refers to a system that can track an object’s position and orientation in space. The GPS systems used in cellular phones are a type of tracking technology that uses satellites for triangulating the position of the object. Although GPS systems are too bulky, slow, and imprecise for HDR brachytherapy, there are other types of tracking systems that can provide sub-millimeter accuracy, are small enough to fit inside of a needle, and have the ability to update the position many times per second.

Over the past decade, electromagnetic (EM) and Fiber-Bragg-Gray (FBG) tracking systems have been investigated for brachytherapy. The EM systems apply the physics of Faraday’s law, whereby a changing magnetic field induces a current through a coiled metallic sensor. The sensor in an EM system records a specific frequency according to its position inside of a magnetic field established by a field generator or an MRI. The FBG system relies on an optical fiber with optical grating patterns that transmit only certain frequencies of light according to how much the fiber has been curved. The shape of the fiber is reconstructed from knowledge of the fiber’s curvature. Researchers have established that these systems are accurate, small, and fast enough to be used for brachytherapy (Sorriento et al., Borot de Battisti et al., Zhou et al., Beaulieu et al.) The researchers have also identified possible clinical workflows. One workflow uses the tracking system to digitize brachytherapy applicators for applicator placement and treatment planning. (Lavallée et al., Beaulieu et al.) Another workflow uses the system as a quality assurance tool to map out the positions of the applicators immediately prior to treatment and compare them with the treatment plan in order to detect digitization errors or movement of the applicator between the end of the implant and the start of the treatment. (Masitho et al., Tho et al., Kallis et al.)

With regards to the vision that was proposed at the start of this post, we are now just beginning to see tracking systems used for real-time dose guidance during applicator placement. An article in Radiotherapy and Oncology by Grajales et al. was published in January and reported the results of a clinical trial for a prototype US-guided prostate HDR system with EM tracking. The system features a treatment planning system that is being engineered for a real-time dose-guidance workflow. This workflow begins with the collection of a 3D US image set and deformable fusion with a pre-existing MRI. The user contours the ptv, urethra, bladder, and rectum, and the system optimizes the positions of the catheters and displays the expected dosimetry. As the needles are placed, the EM-tracked stylet can provide a dual view of EM and MRI images with the needle’s actual position superimposed on each image set. The EM stylet could also provide the user with instant feedback on how far off they are from the ‘ideal’ needle position and how much the dosimetry changed from the preplan. This initial study reported on workflow efficiency and digitization accuracy. The reported efficiency was impressive—an average of 50 minutes from the start of US data collection to final treatment plan approval for whole-gland therapy. The researchers also highlighted that the EM system provided the confidence to use needles that were otherwise difficult to see with US images alone (21% of needles). The digitization accuracy reported by the study was adequate, but there was room for improvement. The system was susceptible to EM noise in the treatment room (namely EM noise from a cellphone carried by the Radiation Oncologist increased calibration errors by nearly 1 mm), and the stylet was bulky and rigid and therefore introduced a systematic deviation in actual vs. reconstructed position because it deformed the curved path of the plastic needles during measurement.

I’m optimistic that we are on the precipice of a new era of brachytherapy, which will leverage tracking technology to streamline the HDR brachytherapy workflow. The devil is always in the details, and the prototype systems will require further optimization in order to provide robust accuracy and efficiency when used by all manner of clinics. Nevertheless, it will be wonderful to one day have a tool that can provide real-time dosimetric guidance for applicator placement. 

References
  • Beaulieu L, Racine E, Han DY, Vigneault E, Hsu IC, Cunha JAM. Real-time electromagnetic tracking-based treatment platform for high-dose-rate prostate brachytherapy: Clinical workflows and end-to-end validation. Brachytherapy. 2018;17(1):103-110.
  • Borot de Battisti MB, Maenhout M, Lagendijk JJW, et al. Fiber Bragg gratings-based sensing for real-time needle tracking during MR-guided brachytherapy. Medical Physics. 2016;43(10):5288-5297. doi:10.1118/1.4961743
  • Grajales D, Kadoury S, Shams R, et al. Performance of an integrated multimodality image guidance and dose planning system supporting tumor-targeted HDR brachytherapy for prostate cancer. Radiotherapy and Oncology. 2022;166:154-161 doi.org/10.1016/j.radonc.2021.11.026
  • Kallis K, Kreppner S, Lotter M, Fietkau R, Strnad V, Bert C. Introduction of a hybrid treatment delivery system used for quality assurance in multi-catheter interstitial brachytherapy. Physics in Medicine and Biology. 2018;63(9):095008. doi:10.1088/1361-6560/aabb5a
 

Brachytherapy and Black History Month
Mitchell Kamrava, MD, MHDS
UCLA
February is Black History month and I’ve learned quite a bit from following Dr. Shearwood McClelland III (@TheDrWood). He’s been featuring a different Black medical pioneer for every day of Black history month. While the people featured by Dr. McClelland are from all medical specialties, several radiation oncologists (Dr. Arnold Malcolm, Dr. Charles Thomas, Dr. Lori Pierce, and Dr. Carl Mansfield) are also celebrated.  All the individuals Dr. McClelland features have made tremendous contributions, but I’d like to take some time to share what I learned about Dr. Carl Mansfield’s impact on the field of brachytherapy. 

Dr. Mansfield was the first Black full professor at Jefferson University in 1974, successfully led 3 departments as chairman (the University of Kansas from 1977-1983, Thomas Jefferson University 1983-1994, and the University of Maryland from 1997-2002), and received the ASTRO Gold Medal. He was also one of the earliest proponents for breast conservation therapy and using breast brachytherapy. Some of his earliest work was published in the journal of Radiology in 1984 on intraoperative interstitial implants of iridium 192 (https://pubmed.ncbi.nlm.nih.gov/6691125/). He subsequently published 10-year results on 654 women treated with interstitial brachytherapy breast boost showing excellent results in an era where mastectomy was standard and women receiving breast conservation often received an electron boost (https://pubmed.ncbi.nlm.nih.gov/7712444/). In his discussion, he outlines the challenges faced with using brachytherapy compared with electrons: “implants require more staff time, expertise, and staff exposure to irradiation”. On the other hand, he clearly saw the advantages of perioperative implantation in that “it is possible to place the implant volume more accurately in the tumor bed. In addition, the implant can be loaded within 3 to 4 hours after the surgery and the overall treatment time is shortened by 2 weeks because it eliminates the need for the electron boost”. Dr. Mansfield was a true brachytherapy pioneer in the development of breast brachytherapy. His challenges with integrating brachytherapy rather than sticking with electrons, because it was a better tool, is reminiscent of our challenges today with integrating brachytherapy.   

For those who are interested in learning more about Dr. Mansfield there is a fantastic interview between Dr. Mansfield and Dr. Nancy Mendenhall and a touching obituary first-authored by Dr. Dwight Heron in the Red Journal:
2022 Annual Conference - Call for Abstracts
We are happy to announce that we have extended the deadline for abstract submissions to April 19th.  At this time, #ABSBrachy22 is scheduled to be an in-person meeting in Denver, CO, June 17 - 19, 2022. Options for remote attendance are under discussion and the outcome will be announced here on the website.

Click here for more information
Calling All Residents
We are looking for ABS member residents to showcase their work in brachytherapy, interesting tips that you have learned, and/or perspectives from a resident. The aim for length is 100-300 words. Please contact Jenna Kahn or Melissa Pomerene if you are interested in next month!
GRU Presents the 32nd International Prostate Cancer Update
Join the International Prostate Cancer Update (IPCU), a multi-day, CME-accredited conference focused on prostate cancer treatment updates. IPCU 32 will feature lectures, interactive panel discussions, debates, and case-based presentations. This conference is led by expert physicians including President-Elect, Peter Rossi, MD, Member at Large, Mira Keyes, MD, and past ABS President, Peter Orio, III, DO, and is designed for urologists, medical oncologists, radiation oncologists, and other healthcare professionals involved in the diagnosis and treatment of prostate cancer.

Click here for more information and register today!
Content Corner


  • HDR Prostate Brachytherapy - Yes, You Can Do It!
  • The webinar will address many issues related to setting up an HDR prostate brachytherapy program. Too often it's easier to come up with reasons why it can't be done. This webinar will address some of the most common hurdles and ways that radiation oncologists with our urologic colleagues can start a successful program. Specific issues will include developing expertise, cost, and working as a team with urologists.




  • Prostate Cancer Radiation Fiducial Marker and SpaceOAR Gel Procedure ABS Virtual Reality (360 VR)
  • This video is filmed in 360VR. On mobile, you can move around the room by moving your phone. On the desktop, you can click and drag the video screen to move around the room. Neil K. Taunk, MD, MS, Radiation Oncologist and Assistant Professor of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania, demonstrates placement of transperineal fiducial markers and SpaceOAR Hydrogel placement for prostate cancer radiotherapy. Fiducial markers are used to guide prostate cancer radiotherapy. SpaceOAR hydrogel may decrease the amount of rectum exposed to prostate radiotherapy. The transperineal approach is used to reduce the risk of infection substantially.
2021-2022 ABS Board of Directors

Ann Klopp, MD, Ph.D., President
Peter Rossi, MD, President-Elect
Brett Cox, MD, Vice President
Kristin Bradley, MD, Treasurer
Christopher L. Deufel, Secretary
Firas Mourtada, Ph.D., Chairman of the Board
Daniel Petereit, Past Chairman of the Board

Directors-at-Large
  
Junzo Chino, MD
Mitchell Kamrava, MD
Mira Keyes, MD
Timothy Showalter, MD