SUO 2024: Novel Approaches to Radiotherapy to Reduce Patient Burden

(UroToday.com) The 2024 SUO annual meeting included a health services session, featuring a presentation by Dr. Ann Raldow discussing novel approaches to radiotherapy to reduce patient burden. Frequent visits for radiotherapy significantly impact patients’ quality of life due to the associated time burden, loss of income, and increased expenses such as gas and parking costs. Moreover, radiotherapy side effects, including urinary, bowel, and sexual dysfunction, have a lasting effect on long-term well-being. Addressing these challenges and reducing the physical, financial, and emotional burdens of treatment can enhance patient adherence and satisfaction. Importantly, newer radiation approaches are transforming how cancer is treated, leading to shorter, more efficient treatments with fewer side effects and greater convenience for patients.

How does radiation kill cancer cells? Dr. Raldow notes that it does so by directly affecting DNA or indirectly by oxidizing water, making free radicals that in turn diffuse towards the DNA and cause damage. Traditional, or conventionally fractionated approaches for radiotherapy, exploit repair differences between the targeted tumor and nearby normal tissue in reaction to the injury caused by a low daily dose of radiation. The improved repair of small, daily fraction injuries within normal tissue compared with the tumor allows for a therapeutic benefit derived from relative tissue repair biology. Giving small daily fractions also allows tumor cells that were in a radioresistant phase of the cell cycle during one treatment to cycle into a sensitive phase of the cycle before the next treatment is given. At the end of a conventionally fractionated radiation course, the goal is for all the cancer cells to have died but for the normal tissue cells to have been given the chance to repair:

Dose escalation, which has been demonstrated to improve outcomes in prostate cancer, can be accomplished with acceptably low toxicity using conformal radiotherapy techniques, but at the expense and inconvenience of delivering large number of fractions, often more than 40 (> 8 weeks). Prostate cancer has a high sensitivity to large fractions of radiation, which may allow for a radically different, radiobiologically-based approach to dose escalation. Novel approaches to radiation therapy aimed at reducing patient burden include hypofractionated and ultrahypofractionated (SBRT) regimens, MR-guided radiation therapy, and adaptive radiotherapy (real-time adjustments based on imaging). Although no longer novel, brachytherapy is an excellent treatment that reduces patient burden.

Delivering a higher dose of radiation per treatment session but with fewer overall sessions, reduces the time patients need to spend undergoing treatment. Clinical studies of hypofractionation in prostate cancer show non-inferior outcomes compared to standard fractionation. The patient benefit is a reduced number of visits from 39 or 40 to as few as 20 sessions. SBRT is a form of ultrahypofractionation, with high doses of radiation therapy delivered with extreme precision over 5 or fewer treatments. Prostate cancer studies show equivalent or better outcomes compared to traditional external beam radiotherapy and the patient benefit is a reduced number of visits from 40+ to as few as 5 sessions:

When hypofractionating prostate cancer treatments, Dr. Radlow notes that it is important to insert rectal spacers, creating a physical separation between the prostate and rectum and therefore reducing rectal toxicity during radiotherapy. An even more novel approach to delivering SBRT is through MR guided radiation therapy. As highlighted below, there is improved image guidance that MR offers as compared to cone-beam CT, which is the traditional image guidance used for radiation therapy courses:

Besides improved image guidance, there are several other reasons to use MR guided radiotherapy, including:

MRI-CT fusion introduces uncertainty
Invasive procedure required to place fiducial markers when using CT guidance
While fiducials allow rigid registration, they provide minimal information regarding organ deformation/motion

We know that a change in rectal size and shape, and/or change in seminal vesicle position, can result in a geographical miss or relative overdose of rectum or bowel without daily adaptive re-planning. Prostate swelling is also known to be significant with SBRT schedules, further strengthening the rationale for daily adaptation. The rationale for using MR-guided radiotherapy in prostate cancer also lies in its ability to provide “real-time” monitoring without the use of additional ionizing radiation, ensuring precise targeting throughout treatment. MR imaging allows for superior visualization of simulation images of critical structures, such as the urethra, enabling more accurate treatment planning. Additionally, MR-guided radiotherapy allows for reduced planning target volume margins by minimizing uncertainties associated with MRI-CT fusion and incorporating gating techniques to account for prostate motion. During treatment, the MRI machine continuously monitors the prostate's position, allowing the radiation beam to be adjusted in real-time to compensate for any movement, ensuring the tumor receives the intended dose while minimizing radiation to surrounding organs:

The phase 3 MIRAGE trial evaluated the efficacy of MRI-guided SBRT compared to conventional CT-guided SBRT in treating localized prostate cancer.¹ The study involved 156 patients randomized to receive either MRI-guided or CT-guided SBRT, both delivering 40 Gy in five fractions. CT guided patients were planned with a standard 4mm planning target volume margin, while MR-guided patients were planned with a 2mm planning target volume margin. The primary endpoint was the incidence of acute grade 2 or higher genitourinary toxicity. A summary of the target volumes and doses is as follows:

ADT (including second generation agents), pelvic nodal radiotherapy, hydrogel placement, and boosting dominant nodules were allowed per investigator discretion. The results demonstrated that MRI-guided SBRT significantly reduced acute grade 2 or higher genitourinary toxicity to 24.4%, compared to 43.4% in the CT-guided group:

Additionally, acute grade 2 or higher gastrointestinal toxicity was 0% in the MRI group versus 10.5% in the CT group. Dr. Raldow notes that these reductions were attributed to the enhanced precision of MRI guidance, allowing for tighter treatment margins and better sparing of surrounding healthy tissues:

Recently, the 2 year outcomes of the MIRAGE trial were published,² noting that the cumulative incidence rates of late grade ≥2 toxicity with MRI-guided versus CT-guided SBRT were 27% versus 51% for genitourinary toxicity (p = 0.004), and 1.4% versus 9.5% for gastrointestinal toxicity (p = 0.025):

MRI-guided SBRT was associated with significantly lower odds of a clinically relevant deterioration in bowel and in the Sexual Health Inventory in Men score:

These findings suggest that MRI-guided SBRT offers superior precision in targeting prostate tumors, leading to reduced toxicity and improved quality of life for patients. Consequently, institutions like UCLA have transitioned to predominantly using MRI-guided SBRT for prostate cancer treatment.

The final novel treatment approach Dr. Radlow discussed is adaptive radiotherapy, which utilizes real-time imaging during treatment to adjust the radiation beam based on tumor movement or changes in anatomy, potentially leading to more precise targeting and reduced toxicity. In the case of prostate cancer, a change in rectal size and shape, and/or change in seminal vesicle position, can result in geographical miss or relative overdose of rectum or bowel without daily adaptive re-planning. Stereotactic magnetic resonance-guided on-line-adaptive radiotherapy (SMART) is a promising tool in the management of many tumors. It not only allows for better soft-tissue contrast and delineation of the tumor and challenging nearby organs at risk, but it also allows for inter-fraction modifications and intra-fraction motion management with real-time treatment gating. We know that SMART has resulted in reduced toxicity in pancreatic cancer and await future outcomes in prostate cancer.

Finally, the EXCALIBUR trial is assessing extremely hypofractionated intensity modulated SBRT for the treatment of prostate cancer with rising PSA after radical prostatectomy. Post-operative CT versus MR-guided SBRT will be tested for patients receiving a 32.5 Gy dose in 5 fractions. Both genitourinary and gastrointestinal 2-year change in patient reported outcomes will be assessed using the EPIC instrument.

Presented by: Ann Raldow, MD, MPH, University of California – Los Angeles, Los Angeles, CA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, between the 3^rd and 6^th of December, 2024.

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