News | Prostate Cancer | September 23, 2019

High-dose Radiation Effective for Men Whose Prostate Cancer Has Spread

Phase II randomized trial data show targeted radiation sparks immune system response similar to vaccination

High-dose Radiation Effective for Men Whose Prostate Cancer Has Spread

September 23, 2019 — A randomized clinical trial of targeted, high-dose radiation for men with oligometastatic prostate cancer has shown the treatment to be an effective and safe option for patients who wish to delay hormone-suppression therapy. The phase II trial found that radiation therapy can generate an immune system response not previously believed possible in this type of cancer. Findings were presented at the 61st Annual Meeting of the American Society for Radiation Oncology (ASTRO), Sept. 15-18, 2019, in Chicago.

Previous research has shown high-dose radiation to be safe and effective for men with localized or non-metastatic prostate cancer, but patients with oligometastatic disease – whose cancer has been treated but then returned to a limited number of other parts of the body – generally have been considered incurable. "Single-institution studies and limited prospective data have recently suggested that high-dose, targeted radiation may be effective for men whose prostate cancer had spread, and now these ORIOLE randomized data confirm those observations," explained Ryan Phillips, M.D., Ph.D., chief resident in radiation oncology at the Johns Hopkins School of Medicine in Baltimore, and lead author on the study. 

The study, also known as the ORIOLE trial, randomized 54 patients whose cancer had spread to a limited number of sites outside the prostate after treatment with surgery or radiation. The patients were placed in one of two arms: those who were observed but received no further treatment for six months, and those who were treated with stereotactic ablative radiotherapy (SABR), also known as stereotactic body radiation therapy (SBRT), to the metastatic sites outside of the prostate. SABR/SBRT is a form of high-precision cancer therapy that delivers substantially higher doses of radiation to the tumor site in just one or a few treatment sessions.

Men treated with SABR were significantly less likely to experience increases in their PSA levels and lived significantly longer without any detectable disease progression than patients who received no additional treatment. Six months later, just 19 percent of patients treated with SABR saw their disease progress, compared to 61 percent of those in the observation arm (p=0.005). The median progression-free survival (PFS) time for those in the observation arm was 5.8 months (HR 0.30, p=0.002), whereas more than half of the patients in the SABR-treated arm were still progression-free more than a year after treatment.

“ORIOLE provides additional randomized trial data to support what previous studies have been suggesting,” said Phillips. “Compared to retrospective reports, our study provides a higher level of evidence that SABR benefits these patients (as compared to observation for six months) because we can see how the patients who didn’t get SABR did in comparison.”

The ORIOLE trial, only the second randomized clinical trial to report findings on SABR for oligometastatic prostate cancer, has also shed light on what happens to the immune system when the disease is treated with high-dose radiation therapy.

The research team looked at blood cells sampled before radiation therapy and 90 days after treatment; they found “significant, measurable changes” in the T cells of patients on the SABR arm, but no change in the T cells of those in the observation arm. “The magnitude of change in the immune system response was similar to what you see after a vaccination” said Phillips, suggesting that radiation may spark the immune system to more aggressively fight the cancer.

“This is the first bit of evidence that I’m aware of showing that SABR can induce a systemic immune response in patients with prostate cancer,” said Phuoc Tran, M.D., Ph.D., principal investigator of the trial and an associate professor of radiation oncology and molecular radiation sciences at the Johns Hopkins Kimmel Cancer Center. “Other studies have made similar observations, but these are probably the most robust, sensitive and controlled observations that SABR can excite a systemic immune response.”

“Cancer of the prostate is a tumor that does not typically incite a response from the immune system, so seeing this response is exciting,” he added. “There is still much work to be done to understand how radiation and the immune system interact.”

Using a sophisticated type of imaging largely accessible only to research institutions, the study also shed light on how high-dose radiation therapy may alter the course of prostate cancer spread or metastasis. 

Typically, metastatic prostate cancer lesions are detected using conventional imaging technologies such as bone scans, magnetic resonance imaging (MRI) and/or computed tomography (CT) scans. The ORIOLE trial used these conventional imaging techniques to identify patients eligible for their study (eligibility was based upon the detection of one to three metastatic lesions), but also made use of a more sensitive, advanced imaging technology known as a prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scan. This scan detects proteins that are overexpressed in prostate cancer and can reveal the presence of otherwise undetectable tumor growth. 

Patients randomized to the SABR arm (n=36) received radiation to all lesions detected by conventional imaging. However, they also underwent PSMA PET scans prior to and 180 days after treatment. The results of those scans were not made available to the physicians developing their treatment plans; they were used only for further analysis and comparison of cancer growth.

What they showed, said Phillips, was that patients with no additional untreated lesions detected by the PSMA PET scan at baseline (a state referred to as total consolidation) were significantly less likely to develop new metastatic lesions at six months (16 percent vs. 63 percent, p=0.006) than those whose PSMA PET scan showed at least one additional lesion at baseline (a state referred to as subtotal consolidation). Patients with total consolidation of lesions also had significantly better (4.8 times greater) progression-free survival than patients whose PSMA PET scans showed additional lesions.

What this suggests, said Tran, is that the high-dose radiation treatments are not just destroying the tumors targeted by SABR, but they are changing the course of metastatic disease.

“Importantly, patients with subtotal consolidation had more new lesions,” he said. “It isn’t just that the untreated lesions are continuing to grow. This phenomenon suggests that treating macroscopic metastatic disease alters the natural history of the disease; that existing macroscopic metastases can influence the non-visible or microscopic disease development into new visible metastases.”

Currently, PSMA PET scans are not widely available for physicians to use in treatment planning, said Phillips, but this study should add to the growing body of evidence of their usefulness. “That extra imaging information gave us extra power to prevent disease progression and new metastases,” he said. “In our experience, these scans add to our ability to control the disease.”

Finally, the trial also analyzed circulating tumor DNA (ctDNA) using an ultra-sensitive liquid biopsy test developed by Max Diehn, M.D., Ph.D., an associate professor of radiation oncology at Stanford University. Using ctDNA, the group identified a specific mutational signature that predicted which men most benefited from SABR. 

“There is now accumulating evidence that SABR is effective for patients with oligometastatic disease, but there are currently no biomarkers that help us to determine who benefits most from this treatment. Our findings represent the first molecular marker that may predict a benefit of SABR in patients with oligometastatic disease. If additional validation of this mutational signature bears out in other cohorts, then we could potentially use it to personalize which patients with oligometastatic prostate cancer should receive SABR,” commented Diehn.

Read more coverage of ASTRO 2019

For more information: www.astro.org

Related Content

(a) A schematic of cycloidal computed tomography (not to scale, seen from top); by adding an array of beam stops in front of the detector, the setup is transformed into an edge-illumination x-ray phase-contrast imaging device. (b) A sinogram sampling grid for a rotation-only scheme. (c) A sinogram sampling grid for a cycloidal scheme. The grids are shown for one mask period and a subset of rotation angles; the combination of empty and filled circles shows the grids that would be achieved through fine latera

(a) A schematic of cycloidal computed tomography (not to scale, seen from top); by adding an array of beam stops in front of the detector, the setup is transformed into an edge-illumination x-ray phase-contrast imaging device. (b) A sinogram sampling grid for a rotation-only scheme. (c) A sinogram sampling grid for a cycloidal scheme. The grids are shown for one mask period and a subset of rotation angles; the combination of empty and filled circles shows the grids that would be achieved through fine lateral sampling (requiring dithering); the filled circles show the data that are sampled without dithering.

News | Computed Tomography (CT) | July 24, 2020
July 24, 2020 — A computed tomography (CT) sca
In I-131 cancer therapy, decay events damage sensitive DNA within a tumor cell nucleus, causing catastrophic single and double strand breaks. Clinical use of antibody-delivered Auger emitters could open a window for the targeted destruction of extracellular COVID-19 virions, decreasing the viral load during active infection and potentially easing the disease burden for a patient. View all figures from this study.  http://jnm.snmjournals.org/content/early/2020/07/16/jnumed.120.249748.full.pdf+html

In I-131 cancer therapy, decay events damage sensitive DNA within a tumor cell nucleus, causing catastrophic single and double strand breaks. Clinical use of antibody-delivered Auger emitters could open a window for the targeted destruction of extracellular COVID-19 virions, decreasing the viral load during active infection and potentially easing the disease burden for a patient. View all figures from this study.

 

News | Coronavirus (COVID-19) | July 22, 2020 | Dave Fornell, Editor
July 22, 2020 — One of the first studies has been published that looks at the use of...
Medical professionals around the world have been feeding lung X-rays into a database since the beginning of the pandemic

Pre-processing results. Image courtesy of Applied Sciences.

News | Coronavirus (COVID-19) | July 22, 2020
July 22, 2020 — Researchers from the Departme
Pioneering study, which included humans, led by Tel Aviv University researchers contradicts widespread conjectures
News | Magnetic Resonance Imaging (MRI) | July 21, 2020
July 21, 2020 — Researchers at Tel Aviv University, led by Prof.

Fig. 1 The basis of high-sensitivity SPION imaging at ultra-low magnetic fields.

(A) Magnetization of 25-nm SPIONs (green), gadolinium CA (Gd-DTPA/Magnevist, blue), and water (red) as a function of magnetic field strength (B0). (B) Magnetization as a function of magnetic field strength (B0) in the ULF (<10 mT) regime for the materials shown in (A). Superparamagnetic materials, such as SPIONs, are highly magnetized even at ULF. Paramagnetic materials, such as CAs based on gadolinium, and body tissues (which typically have diamagnetic susceptibilities close to water) have absolute magnetizations that increase linearly with field strength. Curves in (A) and (B) were reproduced from data in (3253) and reflect the magnetic moment per kilogram of compound. (C) Highly magnetized SPIONs (brown) interact with nearby 1H spins in water, shortening 1H relaxation times, and causing susceptibility-based shifts in Larmor frequency. Image courtesy of Science Advances

News | Magnetic Resonance Imaging (MRI) | July 20, 2020
July 20, 2020 — Lowering the cost of magne...
"Our study demonstrates that a real-world lung cancer screening can perform similar to randomized controlled trials in regard to important performance metrics," the UPenn authors of this AJR article concluded. Image courtesy of American Journal of Roentgenology (AJR)

"Our study demonstrates that a real-world lung cancer screening can perform similar to randomized controlled trials in regard to important performance metrics," the UPenn authors of this AJR article concluded. Image courtesy of American Journal of Roentgenology (AJR)

News | Lung Imaging | July 17, 2020
July 17, 2020 — An online first accepted...
PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

News | PET-CT | July 16, 2020
July 16, 2020 — New research confirms the high impact of...
Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs

Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs using additional physiologically important parameters, for example, glucose transport rate K1 (d), across the entire body. Image courtesy of G.B. Wang, M. Parikh, L. Nardo, et al., University of California Davis, Calif.

News | PET Imaging | July 16, 2020
July 16, 2020 — Results from the first...