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Radiopharmaceutical Therapies: Are we seeing the tip of the iceberg?

By Ana Ponce Kiess, MD, PhD, and Freddy E. Escorcia, MD, PhD
Promoting Science through Research and Training Subcommittee

In the past six years, we have seen FDA approval of three novel radiopharmaceutical therapies (RPTs): Radium-223 for bone metastases of castrate-resistant prostate cancer, [177Lu]Lu-DOTATATE for neuroendocrine carcinomas, and [131I]I-MIBG for malignant pheochromocytoma and paraganglioma. But with [177Lu]Lu-PSMA agents and many other drugs also in clinical development, are we only seeing the tip of the iceberg?

Paul Wallner, DO, FASTRO, recently provided a timely historical perspective and summary of current clinical uses of radiopharmaceuticals in the spring issue of ASTROnews. While the recent ASTRO Scope of Practice survey shows that only 30% of radiation oncologists currently use RPTs, it is one of the areas of highest interest for expanding scope of practice. At the upcoming ASTRO Annual Meeting in Chicago, a half-day Theranostics Training Workshop on Saturday, September 14, will provide a refresher on relevant physics, pharmacology and radiobiology as well as logistical and practical training in clinical use of radiopharmaceuticals. It will include specific breakout sessions on Ra-223, [177Lu]Lu-DOTATATE, [177Lu]Lu-PSMA agents, [131I]I-MIBG and [90Y]Y-Microspheres, and will also cover important infrastructure, workflow and financial considerations.

Ongoing research in RPTs is even more exciting and demonstrates the depth of the “iceberg” under the surface. There are currently more than 200 clinical trials listed in this category on clinicaltrials.gov.  Industry partners are highly committed to the development of RPTs, and academic research has unleashed the potential for combining molecular targeting with the power of radiation to damage DNA and modulate the tumor microenvironment and immune response.

Generally, there are three main pieces of the RPT puzzle: (1) tumor-selective targeting ligands, linked to (2) a chelating group with selectivity for (3) a therapeutic radioisotope. While identifying tumor-specific molecules is very challenging, the advent of next generation sequencing has significantly improved this pursuit, yielding differentially expressed genes in cancers when compared with normal tissue.

Tumor antigen-selective full-length antibodies (~150 KDa) and antibody fragments (25-75 KDa) have been exploited for several decades by pioneers in the field, ultimately resulting in FDA approvals. Newer methods to engineer diverse proteins and peptides of varying sizes with selectivity to virtually any target of interest has resulted in a myriad of molecules that could be used as ligands for RPT agents. Unsurprisingly, the size of these molecules plays a critical role in both the pharmacokinetics of the drug as well as the penetration of solid tumors, and the agents that have received the most interest are peptide (e.g., DOTATATE) or small molecule (e.g., PSMA targeting ligands) based. Engineered antibodies such as minibodies (~75 KDa), single-chain variable fragments (scFvs, ~25 KDa) and single domain antibodies (~15 KDa) have also demonstrated promise as tumor specific ligands for radiopharmaceutical-based imaging and therapy.1-3 Other molecules such as Affibodies and DARPins have also been explored with varying levels of success.

The diversity and quality of radioisotopes available for preclinical and clinical use has also improved. The Department of Energy has made significant commitments toward ensuring that this critical resource is available for domestic development. Investigators typically select the radioisotope physical half-life to match the blood half-life of the scaffold to which it is coupled. One notable feature that has been exploited is the pairing of a diagnostic imaging molecule that can highlight tumor distribution in vivo prior to administration of the therapeutic partner (e.g., same scaffold, different radioisotope). For example, [68Ga]Ga-DOTATATE is the imaging partner to the therapeutic [177Lu]Lu-DOTATATE.

The type of radioactive emission (e.g., beta, alpha) of a given radionuclide is also important and expected to have different therapeutic and safety considerations. The high linear energy transfer (LET) and short path length (a few cell diameters) of alpha-particles, for instance, confers significant potential for tumor cell kill with sparing of surrounding tissue if targeted specifically to tumors. Theory has become reality as specific cases of Ac-225 coupled to PSMA-targeting ligands have resulted in not only radiographic, but also biochemical complete responses, even in patients who were refractory to the same ligand coupled with Lu-177.4-5 However, there is also evidence of increased side effects compared to beta emitters, such as dose-limiting xerostomia with [225Ac]Ac-PSMA agents.6 Recent reports of Pb-212, another alpha-emitter, conjugated to octreotate (the molecule from which DOTATATE is derived) in patients have demonstrated tolerability.

Importantly, significant work remains to be done in standardizing absorbed dose estimates of systemically administered RPTs, accounting for not only radioisotope and ligand particularities, but also heterogeneity in tumor burden across patient populations. Furthermore, systematic assessments of normal organ dose and function in the setting of therapeutic doses of radioisotopes are needed to rival those we use daily for external beam constraints for organs at risk.

As Dr. Wallner highlighted, this is one of several waves of interest in RPTs over the years. However, this generation of emerging RPTs is likely to continue expanding in the context of advances in identifying tumor-selective markers, ligand generation and radioisotope availability. Radiation oncologists, in partnership with our colleagues in nuclear medicine and medical oncology, are poised to deliver the promise of these new agents safely and effectively to our patients.

Do you use radiopharmaceutical therapies in your practice? Please share your experiences in the comments below.

Learn more about the Theranostics Workshop, taking place on Saturday, September 14, at the ASTRO Annual Meeting in Chicago.

Dr. Ana Kiess is assistant professor and residency program director in the Department of Radiation Oncology at Johns Hopkins University. Dr. Freddy Escorcia is an assistant clinical investigator within the Molecular Imaging Program and the Radiation Oncology Branch at the NCI Center for Cancer Research where he heads the Laboratory of Molecular Radiotherapy.

References

  1. Pandit-Taskar N, O'Donoghue JA, Ruan S, Lyashchenko SK, Carrasquillo JA, Heller G, et al. First-in-Human Imaging with 89Zr-Df-IAB2M Anti-PSMA Minibody in Patients with Metastatic Prostate Cancer: Pharmacokinetics, Biodistribution, Dosimetry, and Lesion Uptake. J Nucl Med. 2016;57:1858-64.
  2. Zettlitz KA, Tavare R, Tsai WK, Yamada RE, Ha NS, Collins J, et al. (18)F-labeled anti-human CD20 cys-diabody for same-day immunoPET in a model of aggressive B cell lymphoma in human CD20 transgenic mice. Eur J Nucl Med Mol Imaging. 2019;46:489-500.
  3. Rashidian M, Ingram JR, Dougan M, Dongre A, Whang KA, LeGall C, et al. Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med. 2017;214:2243-55.
  4. Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-Targeted alpha-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2016;57:1941-4.
  5. Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. (225)Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46:129-38.
  6. Kratochwil et al.  225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer. J Nucl Med. 2016;57(12):1941-44.

 

Posted: July 16, 2019 | 0 comments


OIG continues to review IMRT planning

By Jessica Adams, ASTRO Health Policy Analyst

In late May 2019, the Office of Inspector General (OIG) released the Health Care Fraud and Abuse Control Program Report for fiscal year 2018. The OIG continues to focus its attention on intensity-modulated radiation therapy (IMRT) treatment planning services, this time reviewing calendar years 2016 and 2017. In the two years after the initial 2013-2015 audit period, the OIG found $3.7 million in potential overpayments for complex simulations and $1.7 million for other IMRT treatment planning services.

ASTRO has raised concerns with the OIG and the Center for Medicare and Medicaid Services (CMS) several times in recent years, first to highlight the confusion during the 2013-2015 time period regarding this code combination and, second, to explain the complexity of IMRT services. It was not until the 2016 Hospital Outpatient Prospective Payment System (OPPS) Final Rule that CMS explicitly stated that providers cannot bill simulation prior to or during IMRT planning. Because of the confusion the regulatory ambiguity caused, ASTRO urged the OIG not to recoup any payments prior to the 2016 Final Rule.

In January 2017, CMS updated the CPT codes that may not be reported with the development of an IMRT treatment plan. CPT codes 77014, 77280, 77285, 77290, 77295, 77306, 77307, 77321 and 77331, are included in the payment for IMRT treatment planning and should not be reported when provided prior to or as part of developing the IMRT treatment plan. ASTRO released coding guidance to help practices ensure proper billing, and this issue was also covered in the February 2018 Radiation Oncology Reimbursement Reminders (RORRs).

Additionally, CMS has issued resources to clarify billing for IMRT treatment planning services. In a May Medicare Learning Network (MLN) Connects transmittal, CMS reiterated existing coding restrictions associated with CPT code 77301. Members should review these resources and ensure that their practices are billing for IMRT treatment planning services correctly. If your practice is struggling with questions related to IMRT treatment planning services, you may wish to purchase ASTRO’s Radiation Oncology Coding Resource, available in print or as an ebook. The Coding Resource includes information on updated CPT codes effective January 1, 2019, and is available for purchase on the ASTRO website. If you have already purchased the Coding Resource, access it by logging in to your MyASTRO account and clicking on Virtual Meetings/Products under My Resources.

For any questions, contact the ASTRO Health Policy department.

Posted: June 19, 2019 | 0 comments


Introducing New Methodology Guide for Developing ASTRO Guidelines

By: Caroline Patton, Manager of Quality Improvement, and Lisa Bradfield, Senior Manager of Quality Improvement

If you work in the field of radiation oncology, you may have used ASTRO guidelines in your practice, but do you know how these guidelines are developed? To share the process, ASTRO recently developed a methodology guide to offer a high-level overview of the many steps involved in bringing a guideline from topic selection through publication and implementation.

Why did ASTRO write a methodology guide?

One goal of the guide is to communicate the process to various groups, including the general ASTRO membership; new members of the Guidelines Subcommittee and guideline task forces; guideline reviewers; and other societies, especially those who may be interested in collaboration or endorsement of our documents.

The guide is also designed to spotlight recent changes to the guideline development process. ASTRO first began writing guidelines more than a decade ago and the process has evolved over time to align with rigorous standards set by the National Academy of Medicine (formerly, Institute of Medicine) and the Council of Medical Specialty Societies. ASTRO has also incorporated improvements based on member feedback to make guidelines more user-friendly.

What are the key areas of the process?

  • Collaboration – Other societies with an interest in the topic of an ASTRO guideline may participate by partnering on the topic, collaborating by naming representatives and reviewers to the ASTRO project, and/or endorsing the finished guideline.
  • Conflict of interest – ASTRO has a rigorous process for assessing relationships between guideline task force members and companies that may be impacted by the guideline’s recommendations to avoid a real or perceived conflict of interest.
  • Systematic review – Each guideline is supported by a systematic review of the literature. After refinement of the results, selected studies are abstracted into detailed evidence tables, which are published with the guideline for complete transparency.
  • Clinical recommendations – The task force develops recommendations based on the data from the evidence tables and rates the strength of the recommendation and the quality of the evidence for each one. The recommendations also undergo formal evaluation of consensus.
  • Peer review and public comment – All guidelines are formally peer reviewed by topic experts identified by ASTRO and collaborating societies. They are also posted online for public comment during which anyone can provide input. The feedback from both phases of review is used to revise the guideline with the final version approved by ASTRO’s Board of Directors.
  • Post-publication monitoring and updating – Guidelines are reviewed for currency annually beginning two years after publication or at the request of an ASTRO member or participating society, with the goal of revising or reaffirming guidelines about every five years.

What’s changed in the guidelines format?

Readers will see a number of changes in our upcoming guidelines that we hope will make the guidelines easier to use and more valuable for treating patients. These include:

  • Reduced length due to less narrative. Those who want more detail on the studies can consult the evidence tables published with the guideline.
  • Presentation of recommendations in a table format to enhance readability.
  • Revised definitions for quality of evidence that quantify the number and types of studies needed for each quality rating and add an “expert opinion” category for recommendations based on consensus rather than data. References that support the quality rating are also included with the recommendation for greater transparency.
  • Inclusion of a preamble outlining several important elements of the development process to standardize and shorten the introductory sections while making the methods section more focused and specific to each guideline.  

You can see all the steps in the process in ASTRO’s guideline development process overview.

What’s coming in the future?

  • ASTRO will begin to focus more on patient involvement and developing supplemental materials to share the guideline content with patients and improve clinician to patient interaction.
  • ASTRO is also in the very early stages of researching options to promote and disseminate guideline content to physicians, including implementation materials or tools.

Under the leadership of a Guideline Methodology Workgroup, ASTRO is continually evaluating and enhancing how guidelines are developed. If there are other elements of the guideline process or format that ASTRO could improve upon to make them more useful, we would welcome your feedback!

Posted: June 11, 2019 | 0 comments


The Residency Training Landscape, Continued

By Paul Harari, MD, FASTRO, ASTRO Board Chair

In the seven years that I have served on the ASTRO Board in various capacities, our leadership has heard from key stakeholders and discussed and debated many important issues. We’ve discussed the future of brachytherapy and the emerging promise of theranostics and artificial intelligence along with the variability of radiation and cancer biology faculty and the need for common curriculum across residency training programs.

Given the attention this year to residency and training issues, I want to continue the discussion about matters that impact our field. Earlier this year we learned that the ACGME residency training requirements would be updated and that part of the deliberation process included public comments. Given the impact that ACGME rules have within our departments and practices, ASTRO did provide comments on a range of topics.

While we think that by and large the current radiation oncology training requirements are good, we feel there are areas that could be adjusted. Knowing that any changes in ACGME’s residency requirements will impact future residents and the field, I want to give some context to ASTRO’s position on ACGME’s proposed changes to the radiation oncology residency program requirements.

Does Program Size Matter?

ASTRO appreciates the difficulty of identifying the right mix between faculty and residents, particularly when some programs are quite large and others small. The three factors that impact this balance are minimum number of faculty, minimum number of residents, and the faculty-to-resident ratio. We recognize that numeric rules do not guarantee success when it comes to education and training, and that minimum requirements are simply an attempt to strike the best balance.

At one point in time, ASTRO thought the idea of increasing both the minimum number of faculty and the minimum number of residents might be a worthy approach. But after further analysis and discussion, we concluded that there is insufficient data at this time to support an increase in the minimum number of residents. If ACGME elects to share anonymized data about key factors such as ABR pass/fail rates or case logs with information about program size, that may shed further light on the question of whether program size matters. In the absence of such clear data, ASTRO believes four residents is an acceptable minimum.

We do have concerns, however, about the current faculty to resident ratio. We fully support that both the cancer biologist (or radiobiologist) and the medical physicist be considered core faculty. We think that given the increasing complexity of multidisciplinary cancer care, at least four different clinical faculty are needed to provide guidance and knowledge transfer for residents to develop the depth of understanding required for practice. Thus, we recommend that the faculty:resident ratio be increased from 0.67:1 to 1:1 and that it be further clarified that this ratio applies to clinical physician faculty. We think that this size-agnostic metric would help improve quality across all programs.

Resident Experiences

As I stated in my March blog post, ASTRO has an eye toward the future health and growth of the specialty. From this perspective, we are supportive of many of the proposals to update residency program’s case minimums and curriculum.

  • ASTRO supports the proposal to require disease-specific clinical rotations. As multidisciplinary, multimodality treatments and increased sophistication of radiation delivery continue to expand and define the standard of care for many cancer patients, we believe this training is imperative.
  • As we look to the future, we anticipate the need for radiation oncologists to be prepared to manage patients who are receiving theranostics and other radiopharmaceuticals. The ongoing use of Xofigo®, the recent approval of Lutethera® and the imminent approval of a PSMA-targeted radioligand and other novel radiolabeled agents in the pipeline lead us to believe that the current requirements are likely insufficient. We are supportive of this update to increase the minimum number of cases.
  • We have significant concerns about the levels of brachytherapy training, particularly in light of recent reports showing underutilization of brachytherapy for patients with cervical cancer and an associated decline in cure rates. We are concerned that the current intracavitary requirements could be met with vaginal cylinders only and without exposure to tandem-based insertions for cervix or endometrial cancer. We wholeheartedly support this proposed change.
  • We agree with the update for resident scholarly activity to require that the results of investigative projects be submitted for publication. We are hopeful that if residents must submit a manuscript during their residency training, faculty at the institution will provide mentorship guidance to help further residents’ scholarly skills.

 

While ASTRO heard concerns about many of these topics, we had not heard concerns that the current resident training requirements are insufficient for external beam cases. After discussion, ASTRO leadership agreed that the focus in the current requirements related to a maximum of 250 treated patients per year is an appropriate upper limit. We have several concerns with changing the definition of the upper limit to 350 simulations per year. First, this could be ambiguous (e.g., is this initial simulation only or does it include adaptive simulation or verification simulation or boost simulation or even simple/block check simulation)? Second, we are concerned that more than 250 initial simulations (i.e., more than 250 treated patients as per the current definition) will not afford residents ample time to read and learn from each simulated case. In many academic practices, full-time attending physician workload does not exceed 250 initial simulations per year, and thus we think this is a reasonable benchmark for the upper limit of patients treated by a resident.

Looking Towards the Future

Radiation oncology has attracted many hundreds of truly outstanding residents to the field over the last several decades. Despite the most recent match challenges, I strongly believe that the discipline remains vibrant, dynamic, intellectually and emotionally rewarding, and a wonderful blend of cancer biology, technology and compassionate cancer care for cure and/or palliation. The more we engage the voice of our trainees and early career practitioners in the dialogue, the stronger our field can become for future generations of providers and cancer patients.

Posted: May 28, 2019 | 0 comments


Get ready to experience a world-changing Presidential Symposium

By Theodore DeWeese, MD, FASTRO

As president of ASTRO and chair of the Annual Meeting Planning Committee, I am thrilled to share with you the exciting, innovative changes coming to the 2019 Annual Meeting and the totally redesigned Presidential Symposium! ASTRO recognizes that as a Society, we must evolve to match the pace of change in this modern world we live in and we take that seriously — in order to provide our members with innovative, thought-provoking, problem-solving tools and events, the Annual Meeting is undergoing a transformation. The Annual Meeting’s theme, Innovate, Collaborate: Transform, speaks to not only the changes taking place in our field as new technology and research expand our capabilities, but also the changes taking place within the format of the meeting itself.

The Annual Meeting is a must attend for all those working in radiation oncology and the changes planned over the next three years ensure this meeting remains an indispensable event and experiential learning opportunity. Most importantly, these changes incorporate your feedback and we will continue to ask for your participation in shaping the program (more on that below!). You can preview the exciting innovations in our previous post, but for now, I want to give you a sneak peek into the reengineered Presidential Symposium.

A whole new experience

In the past, the Presidential Symposium was a didactic lecture focused on a “deep dive” of a topic. This year, we are unveiling a whole new format centered around this thought-provoking question: “Curing metastatic disease with radiotherapy: Myth or reality?” I am inviting attendees to join me in discussing this provocative, and perhaps polarizing topic using a new concept design for the symposium.

General Session: The first part of the Presidential Symposium will be comprised of three, level-setting talks and an Oxford-style debate, taking place in the general session room. I like to think of this session as your large university lecture hall. The presentations will ensure that all attendees are on the same page as to the state-of the-state when thinking about metastatic cancer. The Oxford-style debate will be a fun and educational dialogue to help unveil and explore where the controversies lie.

Expanded Learning Sessions: Next, attendees will select one of 12 facilitated sessions. I liken these to a smaller university course with much more interaction and discussion during class. Each of the 12 topics will focus on one aspect of the overall debate topic to give attendees an opportunity to “pick a side” they feel most passionate about and get more involved in the debate! Start conversing with your peers and colleagues now and be sure to let us know your feedback on the topics selected thus far, including if we have left out something important!

Table Talks: Following the expanded learning sessions, you will have the opportunity to continue the discussions with informal table talks in the Innovation Hub. These sessions will be more akin to a five to 10-person study group, with high interaction and engagement. And, this is where the real fun begins!

For the first time ever, we are opening a community on ASTRO’s forum, ROhub, for members and industry to start the discussion and shape the topics ahead of the Annual Meeting!

All ASTRO members are invited to opt-in:

  1. Join the PS: Innovate Together community. You’ll need to log in with your ASTRO credentials.
  2. Click the latest discussion post or start your own.
  3. Discuss the expanded learning session topics and start the conversation with your colleagues now. Provide feedback on the various topics and let us know if we’ve missed something important!
  4. Post suggestions for the Table Talk topics and let us know if you are interested in leading a Table Talk.

Members of the community will receive a daily digest of the previous day’s conversations to keep up to date with the latest information. You can change your digest subscription at any time by simply adjusting the “Community Notifications” under the “My Account” tab.

Join us

The Presidential Symposium is just one example of how we’re increasing engagement and collaboration as we raise the profile of radiation oncology and continue to support innovation within our field. You will experience a customized learning event, where you can determine your path and have a unique opportunity to shape the discussion topics. On behalf of the ASTRO Annual Meeting planning committee, I invite you to join us in Chicago for these exciting, ground-breaking changes!

View the video to learn more about the Presidential Symposium.

Learn more about what’s new for the 2019 Annual Meeting from ASTRO CEO Laura Thevenot.

Posted: May 22, 2019 | 0 comments


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