What can PDT does for cancer treatment?

Metastasis is the main cause of death in cancer patients. One route for the spread of metastatic cells is through tumour-associated lymphatic vessels into the lymph nodes. Affected nodes can be removed surgically along with the primary tumour, but tumour cells inside the lymphatic vessels are left behind. Now, researchers from Finland have shown how using photodynamic therapy (PDT) to destroy lymphatic vessels and the tumour cells lodged within can halt the spread of cancer (Sci. Transl. Med. 3 69ra11).

The research team – headed up by Tuomas Tammela of the University of Helsinki – used animal studies to observe the tumour metastasis process in more detail. They implanted mouse melanoma cells into mouse ears and waited up to two weeks for the tumours to reach 1–2 mm in diameter and lymphangiogenesis (the tumour-induced formation of new lymphatic vessels) to set in.

Lymphatic vessel

Immunohistochemistry revealed that the newly formed lymphatic vessels did indeed contain in-transit tumour cells, as well as small tumour nodules. Analysis of tissue sections from a patient with recurrent melanoma demonstrated that lymphatic vessels of cancer patients also contain in-transit tumour cells and nodules.

Tammela and co-workers then investigated whether PDT could selectively destroy lymphatic vessels without affecting surrounding tissue. They injected verteporfin, a photosensitive drug that's used clinically to treat macular degeneration, into the mouse ear. Fluorescence imaging revealed that the drug accumulated preferentially within the lymphatic vessels. Illumination with 689 nm laser light activated the verteporfin, causing the vessels to shrink, fragment and become leaky.

Next, the researchers examined the combination of surgery and PDT. They implanted mouse melanoma cells into the flanks of mice, and waited two weeks for the tumour cells to become established and metastasize to the axillary lymph nodes. They then injected verteporfin into the primary tumour and surrounding tissue and illuminated the entire flank with infrared laser light before surgically removing the primary tumour and lymph nodes. A control group of mice only received the surgical treatment.

Targeting intralymphatic cells

Mice that underwent surgery plus PDT showed a tumour relapse rate of around 10%, compared with 65% for mice receiving surgery alone. This finding indicates that tumour nodules in the lymphatic vessels are a source of relapse, and suggests that targeting in-transit cells may reduce the rate of cancer recurrence in human patients.

"We do not expect PDT to replace current surgical techniques, which comprise removal of the primary tumour and metastatic lymph nodes," Tammela explained. "However, PDT could easily be combined with existing surgical techniques to destroy the lymphatic vessels draining from the tumour, as well as the tumour cell aggregates residing within them." He noted that, as both and PDT are already in use in patients, they are more likely to be approved for targeting tumour-associated lymphatic vessels than drugs in earlier phases of development.

Deep treatment
One limitation of PDT is that it's constrained by the penetration of light into tissue. To evaluate the feasibility of using PDT to destroy lymphatic vessels in humans, the team examined a pig model. To reach the deeper lymphatic vessels, they injected verteporfin into the pig's hoof, and then applied laser light using a "side-fire" laser catheter inserted at the knee. Following irradiation, the pig's lymphatic vessels fragmented and became clogged, indicating that PDT can target vessels deep within the body.

"We have demonstrated that photodynamic targeting of tumour-associated lymphatic vessels and intralymphatic tumour cells prevents locoregional metastasis and eradicates routes of tumour cell dissemination via the lymphatic system," the authors conclude. "Our approach may help to eradicate microscopic tumour cell aggregates in cancer patients and should render anti-lymphangiogenic therapies more feasible for clinical application. 


By: Medicalphysicsweb.org - Research Articles 

Gold seeds with IGRT >>> better cancer treatment

Proton bombardment

As written in the last article, the government of Canada has invested $35 million in four development programs, and the projects are headed up by: TRIUMF (Vancouver, BC); Canadian Light Source (Saskatoon, SK); Advanced Cyclotron Systems (Richmond, BC); and Prairie Isotope Production Enterprise (Winnipeg, MB). So,TRIUMF and Advanced Cyclotron Systems (ACSI) are both working on the cyclotron-based approach, which exploits the direct transmutation of Mo-100 into Tc-99m.

The process works as follows: the cyclotron accelerates hydrogen ions to a prerequisite energy, strips off the electrons to create a proton beam, and then directs this beam onto a thin target of enriched Mo-100. The protons collide with molybdenum nuclei and some of them cause it to transmute into Tc-99m (the proton beam energy is selected to optimize Tc-99m creation and minimize creation of other nuclides). Finally, the Tc-99m is extracted by dissolving the target and passing the solution through an ion-exchange column.

It's not a new idea – this method has been known for over 40 years – but, according to TRIUMF's Timothy Meyer, scaling up to efficient high-volume production requires the development and validation of several key processes.

"You need to show that the fabrication of the Mo-100 target is economical and reproducible, and that the accelerator can deliver sustained power levels in a reliable and efficient manner," he explained. "You also want to show that the separation and purification technologies meet regulatory guidelines for purity and clinical performance."

The TRIUMF team – known as CycloTech⁹⁹ – is investigating Tc-99m production on three different types of cyclotron. The idea is to use existing hospital cyclotrons, which currently produce other medical isotopes, to produce Tc-99m and distribute it to local clinics. Such cyclotrons will need to be upgraded, in particular by adding a beamline that's capable of irradiating solid targets. "We're going to benchmark the price and performance of that upgrade process and how it varies on different cyclotrons," Meyer said.

Myocardial perfusion imaging

Importantly, says Meyer, the upgrade won't impinge upon the normal cyclotron operating cycle. "Most medial isotope cyclotrons don't run 24 hours a day, they produce PET isotopes with short half-lives at certain schedules during the day," he explained. "The strategy would be to irradiate Mo-100 overnight, and then transfer it to the laboratory in the morning to process the Tc-99m shipment for the day."

Cyclotron manufacturer ACSI is also working to optimize this method of Tc-99m production, and has teamed up with the Centre Hospitalier Universitaire de Sherbrooke in Quebec and the University of Alberta. The collaboration has already made progress in target and process development, with Curie amounts of Tc-99m created using existing cyclotrons at the two facilities.

Quality control tests have shown that the cyclotrons can produce clinical-grade Tc-99m. Research will now focus on developing cost-efficient production using ACSI's high-current 24 MeV cyclotrons. Similarly to TRIUMF, the ultimate aim is to establish a decentralized network of medium-energy cyclotrons capable of producing large quantities of Tc-99m.

Photoneutron focus

The other two teams - Prairie Isotope Production Enterprise (PIPE) and Canadian Light Source – are developing production methods based around an electron accelerator. Again, Mo-100 is used as the target, but in this case, photoneutron reactions create Mo-99 as the end product.

High-energy electrons from a linear accelerator are incident upon the Mo-100 target, usually via a metal filter that helps dissipate the heat from the electron beam and creates a beam of intense X-rays. The X-rays remove a single neutron from some of the Mo-100 atoms in the target – turning them into Mo-99.

"Right now, we're using a water-cooled tungsten converter in front of natural molybdenum samples," PIPE's Jeff Martin explained. He noted that the team is also considering direct electron-beam irradiation, but that this can create problems with heating. PIPE is also looking at a range of methods for extracting the radioisotopes from the irradiated target.

"The idea we're working the hardest on involves dissolving the molybdenum target in solution. The solution will also contain Tc-99m, which can then be separated via a solvent extraction technique," said Martin. "The advantage of this method is you get very little breakthrough of non-radioactive molybdenum, a heavy metal that you don't want to give to the patient."

Martin pointed out that PIPE plans to speed its production process to market by basing it mostly on commercially available technologies. The collaboration has already shipped Mo-99 twice to the Health Sciences Centre in Winnipeg. "They've dissolved and extracted Tc-99m and it looks like it works," added John Barnard, Acsion Industries' director of research and technology.

One challenge associated with both the accelerator- and cyclotron-based approaches is the cost of the Mo-100 targets. Mo-100 comprises less than 10% of naturally occurring molybdenum and currently costs over $1000 per gram. Thus Tc-99m manufacture must also involve reprocessing of the irradiated targets.

"Because you only activate a small part of the Mo-100 in each cycle, it has to be recovered and integrated into a recovery process, which is an added complication to the whole isotope use in hospitals," explained Barnard. "That is going to be challenging - whether you use cyclotron or accelerator."

Looking ahead

The teams now have 15 months to prove themselves. After that, successful technologies could be rolled out across Canada and then marketed worldwide, possibly exploiting industry partnerships private to help with licensing and commercialization. Time will tell which will scale the fastest and prove the most reliable and economical. Either approach would create a more distributed supply network that overcomes the vulnerabilities of the current supply chain.

In terms of practical implementation, the cyclotron-based method produces Tc-99m, which has a half-life of just six hours and must therefore be manufactured at or very near to clinical sites. This approach can, however, take advantage of a wide network of existing medical cyclotrons.

The electron accelerator approach creates Mo-99, which has a half-life of 66 hours and, as such, can be shipped. "One or two linacs could probably supply most of Canada," Barnard said. This method also benefits from being more similar to, and thus able to exploit, the existing Tc-99m supply chain based on shipping of Mo-99.

"The decision by the government of Canada to invest public funds in a technology development programme is quite bold," Meyer told medicalphysicsweb. "If it's successful, with a few of these technologies at scale within about 15 months, the government's strategy and its faith in the technical community will be validated."

Kill Cancer By New Tech: Tc-99m production: losing the reactor

Kill Cancer By New Tech: Tc-99m production: losing the reactor

Tc-99m production: losing the reactor

Medical Cyclotron

Technetium-99m (Tc-99m) is the most widely used medical imaging isotope, employed in more than 30 million procedures worldwide each year. The isotope is created via decay of molybdenum-99 (Mo-99), which itself is produced in nuclear reactors. And herein lies the problem.

The nuclear reactor is needed to generate neutrons that bombard uranium-235 targets, with the resulting fission reaction producing Mo-99 around 6% of the time. This Mo-99 then decays into Tc-99m. Unfortunately, over 90% of the world's Mo-99 is produced by just five ageing reactors, resulting in an extremely fragile supply chain - the vulnerability of which was highlighted recently when unexpected shutdowns and routine maintenance closures combined to create serious shortages. But there are other ways to create Tc-99m, and ways that don't require nuclear reactors or a uranium target – itself a cause for concern as most facilities currently process highly-enriched (weapons-grade) uranium. Instead, researchers are investigating production methods based on cyclotrons and linear accelerators. Such processes exploit nuclear reactions within targets of Mo-100, bypassing the need for uranium completely.

In a bid to advance such technologies, the government of Canada has invested $35 million in four development programmes. The projects are headed up by: TRIUMF (Vancouver, BC); Canadian Light Source (Saskatoon, SK); Advanced Cyclotron Systems (Richmond, BC); and Prairie Isotope Production Enterprise (Winnipeg, MB) – a partnership between the University of Winnipeg, Acsion Industries and Health Sciences Centre Winnipeg.

"If Canada was going to build a new nuclear reactor, it'd cost a billion dollars," said Jeff Martin, professor of physics at the University of Winnipeg. "But with these proposed electron accelerators and cyclotrons, you have a smaller capital investment and can be up and running fast."

Read about Proton bombardment in the next article.

About the author 

Tami Freeman is editor of medicalphysicsweb.