Jul 5, 2012
Optimizing peptide receptor radiotherapy
Peptide receptor radiotherapy uses radiolabelled peptides to deliver radioactivity directly to tumours. The technique is often used as a second- or third-line treatment for metastatic neuroendocrine cancer, where most patients display a combination of large heterogeneous tumours and undetectable millimetre-sized metastases.
Larger tumours are best treated using long-range beta emitters, such as 90Y, while shorter-range emitters such as 177Lu are more suitable for treating small tumours. A 90Y-177Lu combination should, in principle, be able to simultaneously treat all lesions, and clinical trials using this combination are now emerging.
Such trials use 90Y-177Lu activity ratios of 70:30 and 50:50, but according to a team from Université Catholique de Louvain in Belgium, patients may benefit from a more individualized radionuclide combination. The researchers also suggest that other beta emitters with longer ranges may prove superior to 90Y. To test these hypotheses, they performed simulations comparing the tumour control probability (TCP) of various radionuclide combinations for a range of tumour models (Phys. Med. Biol. 57 4263).
"In the external-beam radiotherapy community, it's long-known that disease control probability displays a sharp dependence on the tumour's absorbed dose. As a consequence, every gray delivered to the tumour is precious for patient outcome and all strategies to optimize this delivery are deployed," explained researcher Stephan Walrand. "It is the duty of physicists to emphasize that the issues are similar in internal radiotherapy."
Walrand and colleagues first derived dose deposition kernels for 177Lu and the long-range beta emitters 148Pm, 90Y, 93Y and 125Sn. These were used to create voxel-based dose distributions of the various radionuclide combinations for nine homogeneous spherical tumours (1–25 mm diameter) and four spherical tumours containing lattices of cold spheres (of 1, 3, 5 and 7 mm diameter). In all cases, a constant biological effective dose of 11 Gy per cycle to the renal cortex was maintained to minimize toxicity and similar pharmacokinetics were assumed.
The researchers then calculated TCP values for all radionuclide combinations. Results demonstrated a clear benefit of using a combination of beta emitters. For example, for a mean tumour absorbed dose of 180 Gy, 90Y-177Lu (in a 25:75 activity ratio) could simultaneously control 2 mm tumours and tumours with 3 mm heterogeneities, with a TCP of better than 90%. This combination of 75% 177Lu and 25% 90Y provided a 50-50 renal cortex absorbed dose from each radionuclide.
Superior performance was seen from 125Sn-177Lu (with a 20:80 activity ratio), which simultaneously controlled 1 mm tumours and tumours with 5 mm heterogeneities for 180 Gy absorbed dose. At 200 Gy, this combination could control 1 mm tumours and 7 mm heterogeneities. The lowest TCP was seen for 93Y-177Lu, due to its short half-life, while 148Pm was better than 90Y but inferior to 125Sn
Looking in more detail at the 25 mm sphere with 3 mm heterogeneities treated with 125Sn-177Lu, the voxel dose distribution revealed that pure 125Sn provided the best irradiation of the cold spheres and the region between them, while pure 177Lu provided the best irradiation of the sphere's inner edge.
The researchers also examined the required tumour specific activity to ensure 90% TCP for the different tumours. For the same tissue uptake and constant renal cortex dose, 90Y-177Lu required an uptake corresponding to 40 Gy more than that required by 125Sn-177Lu to control the 1 mm tumour and 7 mm heterogeneities.
Finally, they studied disease control probability as a function of 177Lu-125Sn proportions, for two patients with a 25 mm heterogeneous tumour, one of whom also had 10 1 mm homogeneous tumours and one who had just one such 1 mm tumour. A small difference in the optimal 177Lu-125Sn ratio was seen between the two patients, in favour of increased 177Lu for the patient with 10 tumours. For this patient, the tumour-specific activity also influenced the optimal ratio, further emphasizing the need for individualized treatment.
The authors note that previous studies have shown large differences in renal uptake between patients, necessitating assessment of this factor for each radionuclide and each patient in order to inject the most efficient safe dose. In supplementary material to the research paper, they provide a program that can compute the required specific activity for a patient's individual tumour parameters.
"Commercial software provided with modern SPECT/CT and PET/CT systems can individually quantify the critical tissue uptakes that determine the maximal safe activity that can be injected," explained Walrand. "For the time being, the spatial resolution and sensitivity of imaging systems are too low to individually assess the uptake distribution inside large tumours and to detect millimetre metastases. However, for each cancer type and stage, a standard intra-tumour uptake pattern could be obtained after curative ablations, and a standard number of undetectable metastases could be deduced from follow-up."
The researchers concluded that clinical trials should employ radionuclide proportions tuned to individual patient dosimetry and that 125Sn is the best for combining with 177Lu. "Pre-clinical studies should now be initiated in order to search for a tin-labelled-peptide with pharmacokinetics at least as good as those of yttrium-DOTATOC," added Walrand.
• Related articles in PMB
Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn–177Lu is superior to 90Y–177Lu in peptide receptor radiotherapy
Stephan Walrand et al Phys. Med. Biol. 57 4263
A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions
N Lanconelli et al Phys. Med. Biol. 57 517
Comparison of yttrium-90 quantitative imaging by TOF and non-TOF PET in a phantom of liver selective internal radiotherapy
Larry van Elmbt et al Phys. Med. Biol. 56 6759
About the author
Tami Freeman is Editor of medicalphysicsweb.