Immunotherapy, Adaptive Radiation Therapy, Novel Radiation Technologies, and Emerging Targets

The goal of the PRADO trial was to understand the feasibility of using the pathologic response to neoadjuvant immunotherapy with ipilimumab and nivolumab to guide further treatment in patients with high-risk, stage III melanoma. 99 patients with node-positive melanoma received neoadjuvant immunotherapy. Using a marker placed in an index lymph node prior to treatment, a lymph node was excised and examined for degree of response. The pathologic nonresponders (n = 21) and partial responders (n = 8) underwent a therapeutic lymph node dissection, where all lymph nodes surrounding the index lymph node are surgically removed. After this procedure, only nonresponders (n = 17) received nivolumab or BRAF/MEK inhibitors ± radiation therapy. Researchers found that the partial responders who did not receive adjuvant therapy had a 24-month recurrence-free survival rate of 64%, whereas nonresponders with adjuvant therapy had a recurrence-free survival rate of 71%.

Cholangiocarcinoma is an aggressive cancer that originates in the bile duct either within the liver or in the extrahepatic biliary tree. Often, these cancers present late, which can preclude patients from undergoing the mainstay of treatment, surgical resection. Self-expandable metallic stents have been used in combination with chemotherapy to treat unresectable cholangiocarcinoma to help maintain patency of the bile duct and treat the cancer. More recently, radiation-emitting metallic stents (REMS) have been developed to promote cancer regression and prevention of malignant obstruction. This randomized controlled trial compared the 2 methods and assessed the safety and efficacy of REMS, and 126 patients were assigned to either arm. The primary endpoint, overall survival, was significantly improved in the REMS arm (10.2 vs 6.7 months). Secondary endpoints included functional scores and symptom control. Patients treated with the REMS with chemo showed improved functional status and decreased fatigue, though severe adverse events and jaundice were not significantly different between the 2 groups.

Thirty-one patients with prostate cancer treated with online adaptive radiation therapy (oART) on an AI-integrated linac were analyzed and grouped by nodal involvement. For prostate-only cases, clinical target volume (CTV)1 (prostate and seminal vesicles) used 5 mm margins (8 mm caudal) to form planning target volume (PTV)1; nodal cases added pelvic nodes (CTV2) with 5 mm isotropic margins (PTV2). Daily cone-beam CT scans (CBCTs) were acquired; organs at risk (OARs; rectum, bladder, bowels) were automatically segmented by AI, and targets were manually delineated. For each fraction, a “predicted” plan (original fluence on daily anatomy) was compared with an “adapted” plan (full reoptimization) using daily dose-volume histogram (DVH) indicators: PTV (V95%), CTV (D98%), bladder (V65Gy), bowel (V45Gy), and rectum (V50Gy). oART improved prostate coverage in both groups (+10.4% and +11.8% in PTV V95%; +2.6% and +2.9% in CTV D98%). Gains for nodal targets were smaller (+3.1% PTV2 V95%; +2.2% CTV2 D98%). OAR differences were not statistically significant (P > .1). Median treatment time was 25 minutes (prostate-only) and 32 minutes (with nodes). Conclusion: oART improved target coverage without significant OAR differences.

STAR is a noninvasive treatment for refractory ventricular tachycardia (VT). After PROSPERO registration (CRD42023439666), databases were searched on November 9, 2023, for prospective STAR trials. 10 trials (82 patients, treated 2016-2022) were included. Risk of bias was assessed with ROBINS-I; meta-analysis used generalized linear mixed models. The 90-day rate of treatment-related grade ≥3 adverse events was 0.10 (95% CI 0.04-0.20). Among 63 evaluable patients, VT-burden reductions were achieved in 0.61 (≥95%), 0.80 (≥75%), and 0.90 (≥50%). 1-year overall survival was 0.73 (95% CI 0.61-0.83; n = 81); 1-year freedom from recurrence 0.30 (95% CI 0.16-0.49; n = 61); and 1-year recurrence-free survival 0.21 (95% CI 0.08-0.46; n = 60). Limitations include methodological heterogeneity and moderate-to-significant risk of bias. Conclusion: STAR shows moderate toxicity and substantial VT-burden reduction in many patients, but high 1-year recurrence supports its investigational status within prospective trials.

This planning study proposes a simulation-free pre-treatment workflow for prostate oART on an MR-Linac using previously acquired diagnostic T1w/T2w MRI to create a reference plan without clinician input. Patients treated with 36.25 Gy in 5 fractions within the HERMES trial were retrospectively assessed for eligibility; targets and OARs were autosegmented, and online plan adaptation was simulated using existing clinical treatment images. Adapted plans were compared with clinical plans; synthetic-CT accuracy was evaluated. Of patients assessed, 87.5% had suitable diagnostic scans. Reference images and treatment plans were successfully created. Simulated online plans met mandatory clinical goals for target dose and conformality without detriment to OAR dose or plan deliverability. Synthetic-CT accuracy was high (gamma 2 mm/2% > 98.9%). Conclusion: non-RT diagnostic MRI can support reference prostate planning on the MR-Linac, producing clinically equivalent adapted plans vs traditional simulation-based planning, with potential time and resource savings.

The progression and recurrence of glioblastoma, a highly aggressive and deadly form of brain cancer, is largely driven by a population of cells known as glioma stem cells (GSCs). These GSCs are supported by vascular endothelial (VE) cells, which provide the nutrition, oxygen, and paracrine factors to support GSC cells. One such factor primarily secreted by VE cells is Endocan, a proteoglycan that helps enhance the proliferation, migration, and angiogenic properties of GBM cells. This study also demonstrated that Endocan contributed to GBM cell survival following radiation therapy as cells pretreated with Endocan had significantly decreased radiation-induced DNA damage based on decreased γ-H2AX (a marker for DNA double-stranded breaks) staining intensity. The proposed mechanism through which these effects occur is by Endocan binding PDGFRA to activate downstream signaling pathways.

However, inhibiting this PDGFRA pathway by either knockdown of PDGFRA or use of PDGFRA inhibitors decreased the effect of Endocan on GBM cells and reduced its proproliferative impacts. Ultimately, Endocan or its downstream signaling pathways are emerging as new potential targets for GBM therapies.

Generally, brain metastases have been treated with postoperative stereotactic radiosurgery (SRS) as it improves local control of the tumor. However, this treatment avenue can cause increased rates of leptomeningeal disease (LMD) and radionecrosis (RN), so this international study explored the potential risks and benefits of neoadjuvant SRS (NaSRS) as an alternative option. Of the 179 patients (and 189 brain metastases) enrolled from across 5 countries, 53% had single fraction NaSRS while 47% had multi-fraction treatment. The endpoints of interest that were explored included local recurrence (LR), any grade of RN, or nodular LMD. The composite endpoint of these 3 markers at 12 months was 8.0% while LR alone was 4.6%, RN of any grade was 3.6%, and nodular LMD was 1.2%. These findings provide support for further study of NaSRS as an emerging treatment avenue based on the low rates of LMD, RN, and LR observed. Additionally, this study indicates that single- and multi-fraction doses of NaSRS can promote similar LR outcomes in patients with brain metastases also undergoing resection.