The primary goal of radiotherapy is to effectively destroy the tumour while minimizing side effects to nearby normal tissues. Focusing on the challenging case of pancreatic cancer, a research team headed up at Toronto Metropolitan University in Canada has demonstrated that gold nanoparticles (GNPs) show potential to optimize this fine balance between tumour control probability (TCP) and normal tissue complication probability (NTCP).
GNPs are under scrutiny as candidates for improving the effectiveness of radiation therapy by enhancing dose deposition within the tumour. The dose enhancement observed when irradiating GNP-infused tumour tissue is mainly due to the Auger effect, in which secondary electrons generated within the nanoparticles can damage cancer cells.
“Nanoparticles like GNPs could be delivered to the tumour using targeting agents such as [the cancer drug] cetuximab, which can specifically bind to the epidermal growth factor receptor expressed on pancreatic cancer cells, ensuring a high concentration of GNPs in the tumour site,” says first author Navid Khaledi, now at CancerCare Manitoba.
This increased localized energy deposition should improve tumour control; but it’s also crucial to consider possible toxicity to normal tissues due to the presence of GNPs. To investigate this further, Khaledi and colleagues simulated treatment plans for five pancreatic cancer cases, using CT images from the Cancer Imaging Archive database.
Plan comparison
For each case, the team compared plans generated using a 2.5 MV photon beam in the presence of GNPs with conventional 6 MV plans. “We chose a 2.5 MV beam due to the enhanced photoelectric effect at this energy, which increases the interaction probability between the beam and the GNPs,” Khaledi explains.
The researchers created the treatment plans using the MATLAB-based planning program matRad. They first determined the dose enhancement conferred by 50-nm diameter GNPs by calculating the relative biological effectiveness (RBE, the ratio of dose without to dose with GNPs for equal biological effects) using custom MATLAB codes. The average RBE for the 2.5 MV beam, using α and β radiosensitivity values for pancreatic tumour, was 1.19. They then applied RBE values to each tumour voxel to calculate dose distributions and TCP and NTCP values.
The team considered four treatment scenarios, based on a prescribed dose of 40 Gy in five fractions: 2.5 MV plus GNPs, designed to increase TCP (using the prescribed dose, but delivering an RBE-weighted dose of 40 Gy x 1.19); 2.5 MV plus GNPs, designed to reduce NTCP (lowering the prescribed dose to deliver an RBE-weighted dose of 40 Gy); 6 MV using the prescribed dose; and 6 MV with the prescribed dose increased to 47.6 Gy (40 Gy x 1.19).
The analysis showed that the presence of GNPs significantly increased TCP values, from around 59% for the standard 6 MV plans to 93.5% for the 2.5 MV plus GNPs (increased TCP) plans. Importantly, the GNPs helped to maintain low NTCP values of below 1%, minimizing the risk of complications in normal tissues. Using a conventional 6 MV beam with an increased dose also resulted in high TCP values, but at the cost of raising NTCP to 27.8% in some cases.
Minimizing risks
The team next assessed the dose to the duodenum, the main dose-limiting organ for pancreatic radiotherapy. The mean dose to the duodenum was highest for the increased-dose 6 MV photon beam, and lowest for the 2.5 MV plus GNPs plans. Similarly, D2%, the maximum dose received by 2% of the volume, was highest with the increased-dose 6 MV beam, and lowest with 2.5 MV plus GNPs.
It’s equally important to consider dose to the liver and kidney, as these organs may also uptake GNPs. The analysis revealed relatively low doses to the liver and left kidney for all treatment options, with mean dose and D2% generally below clinically significant thresholds. The highest mean doses to the liver and left kidney for 2.5 MV plus GNPs were 3.3 and 7.7 Gy, respectively, compared with 2.3 and 8 Gy for standard 6 MV photons.
The researchers conclude that the use of GNPs in radiation therapy has potential to significantly improve treatment outcomes and benefit cancer patients. Khaledi notes, however, that although GNPs have shown promise in preclinical studies and animal models, they have not yet been tested for radiotherapy enhancement in human subjects.
Next, the team plans to investigate new linac targets that could potentially enable therapeutic applications. “One limitation of the current 2.5 MV beam is its low dose rate (60 MU/min) on TrueBeam linacs, primarily due to the copper target’s heat tolerance,” Khaledi tells Physics World. “Increasing the dose rate could make the beam clinically useful, but it risks melting the copper target. Future work will evaluate the beam spectrum for different target designs and materials.”
The researchers report their findings in Physics in Medicine & Biology.
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