Adaptive radiotherapy has great potential to provide cancer patients with more precise and personalized treatment than was possible before. With artificial intelligence driving the treatment and planning processes, adaptive radiotherapy enables clinicians to adapt a patient’s treatment plan each day based on tumor and anatomical changes, so that dose distributions are more conformal than can be achieved with non-adaptive approaches to radiotherapy.
“As of February, 2023, 65 of 141 Ethos™ adaptive therapy systems ordered by clinical sites around the world had been installed and used to deliver over 58,000 online adaptive treatment sessions,” said Sasa Mutic, PhD, Senior Vice President, Radiation Treatment Solutions at Varian. “Adaptive plans were chosen over the original treatment plan some 85.6 percent of the time. These AI-driven adaptive treatments typically took about 20 minutes to complete.”1
As with the early days of IMRT, the question remains: does adaptive radiotherapy make a difference to clinical outcomes for patients? Will it allow margin reductions? Will it reduce toxicities? To find out, Varian is investing in two kinds of clinical research—Varian-sponsored clinical trials and investigator-initiated studies.
Varian-Sponsored ARTIA Clinical Trials
In 2022, Varian announced the ARTIA clinical research program, which is a portfolio of Varian-sponsored clinical trials on adaptive radiotherapy. The acronym stands for: Adaptive Radiation Therapy using an Individualized Approach. “As we designed the ARTIA clinical research program,” said Ricky Sharma, MD, PhD, Vice President, Medical Affairs at Varian, “it was important to focus on tumor sites for which we could measure meaningful clinical endpoints to compare against pre-existing studies within a reasonable timeframe.”
Each trial was developed in collaboration with lead investigators (oncologists and medical physicists) who provided clinical insights for the trial design as well as technical expertise for implementing the optimal approach for daily adaptation. Protocols were reviewed by members of the Adaptive Intelligence™ Consortium (AIC), a global community of clinicians and scientists from leading cancer clinics working to develop best practices for adaptive radiotherapy based on clinical evidence. This ensured that the studies are broadly applicable and will yield clinically usable information across diverse oncology treatment settings.
As a result of those conversations, seven clinical trials were developed, two on treating cancers of the bladder and one each addressing cancers of the cervix, lung, prostate, pancreas, and head & neck. As of March 2023, five of the seven clinical trials were open and enrolling study participants. Primary endpoints incorporated either physician-reported or patient-reported toxicity outcomes (see table below).
|Trial Name||Disease||Lead site||Primary Endpoint|
|ARTIA-Vesica||Muscle-invasive bladder||Herlev and Gentofte Hospital, Copenhagen, Denmark||Physician-reported acute GI toxicity|
|ARTIA-Bladder||Muscle-invasive bladder||Washington University, St. Louis, MO, USA||Physician-reported acute GI/GU toxicity|
|ARTIA-Cervix||Locally advanced node-negative cervix||University of California, San Diego, CA, USA||Patient-reported acute GI toxicity (PRO)|
|ARTIA-Lung||Stage III non-small cell lung||University of Alabama, Birmingham, AL, USA||Patient-reported acute composite toxicity (PRO)|
|ARTIA-Prostate||Low- and intermediate-risk prostate||Brigham and Women’s Hospital, Boston, MA, USA||Patient-reported acute urinary toxicity (PRO)|
|ARTIA-Pancreas||Locally advanced pancreas||Washington University, St. Louis, MO, USA||Physician-reported acute GI toxicity|
|ARTIA-H&N||Locoregionally advanced head and neck||Moffitt Cancer Center, Tampa, FL, USA||Physician-reported mean acute toxicity burden|
“These studies primarily examine reduction in toxicities for patients during and after radiotherapy, and they also incorporate secondary endpoints evaluating cancer outcomes and quality of life. We anticipate the evidence generated by the ARTIA clinical research program will show that adaptive therapy is a fundamental advance for patients by reducing toxicities while optimizing cancer outcomes,” Dr. Sharma elaborated.
Investigator-Initiated Trials Covering Adaptive Radiotherapy
In parallel with the ARTIA program, Varian is providing support through its research grants program to institutions around the globe that are conducting their own adaptive radiotherapy trials. These investigator-initiated studies (IIS) cover a wide range of novel approaches for utilizing the Ethos platform. There are currently 21 investigator-initiated studies of Ethos opened or planned at 13 institutions, covering numerous disease sites including head & neck, brain, breast, lung, rectum, bladder, prostate, vulva, cervix, anus, melanoma, bone metastases and oligometastatic disease.
“Many of the investigator-initiated studies evolved from the innovative concepts generated amongst AIC members during the initial planning phase of the ARTIA studies,” said Heather Curry, MD, Senior Director of Global Evidence and Value, and member of the Medical Affairs team at Varian. “These are generally smaller, single institution studies with planned enrollment ranging from 1-100 participants and investigate highly individualistic techniques that may not necessarily lend themselves to the consensus required for study under a consortium approach. The investigator-initiated trials focus on the feasibility, safety, and early clinical experience of Ethos first adopters as they implement these novel techniques and workflows.”
For example, one trial carried out at Amsterdam University Medical Center sought to evaluate the feasibility of implementing a rapid workflow by omitting the treatment planning CT for patients with metastatic bone disease. The treatment plans were instead generated using the prior diagnostic CT-scans and were then adapted on-couch to the patients’ positioning and anatomical changes by using Ethos adaptive radiotherapy (ART). This workflow enabled patients to be treated with highly conformal IMRT plans within two hours after consultation on the day of their first visit. “For several bed-bound patients, this approach significantly decreased travel burden of two visits and the waiting times associated with our routine OSS procedure,” the researchers report.2
Many other researchers have begun to present and publish data about adaptive treatment quality,3 the adaptive process and workflow,4 adaptive dosimetry relative to non-adaptive plans, and many other topics that can help other treatment teams think through their own plans for therapy. “Our hope is that the clinical evidence will show that adaptive therapy benefits a broad spectrum of patients,” Dr. Curry added.
1Data on file at Varian, analysis based on 76 institutions in EMEA, APJI, and Americas from September 2019 through February 2023
2Nelissen KJ, Versteijne E, Senan S, Rijksen B, Admiraal M, Visser J, Barink S, de la Fuente AL, Hoffmans D, Slotman BJ, Verbakel WFAR. Same-day adaptive palliative radiotherapy without prior CT simulation: Early outcomes in the FAST-METS study. Radiother Oncol. 2023 Feb 16;182:109538. doi:
3Åström, L.M., Behrens, C.P., Calmels, L., Sjöström, D., Geertsen, P., Mouritsen, L.S., Serup-Hansen, E., Lindberg, H., Sibolt, P., Online adaptive radiotherapy of urinary bladder cancer with full reoptimization to the anatomy of the day: initial experience and dosimetric benefits, Radiotherapy and Oncology (2022), doi:
4S. Azzarouali, K. Goudschaal, D. den Boer, J. Visser, M. Hulshof, A. Bel. AI-based online adaptive CBCT-guided radiotherapy for bladder cancer using SIB and fiducial markers. European Society for Radiotherapy and Oncology, Copenhagen, Denmark, 2022.