The Future of PRRT in the USA

Ebrahim Delpassand, Chairman and Medical Director, Excel Diagnostics and Nuclear Oncology Center, Houston, TX addressed attendees at the 11/11/11 Worldwide NET Cancer Awareness Day event sponsored by Caring For Carcinoid Foundation and M.D. Anderson Cancer Center in Houston.

Dr. Delpassand has worked more diligently than any person I know, to bring one of Europe's prize treatments to NETs patients in the US. At an earlier conference, before he secured FDA approval to use 177-Lutetium, he described the extremely difficult process of his application to investigate a new drug (IND) with the FDA. It sounds like a needlessly complicated and frustrating ordeal.

In January 2011, Excel Diagnostics was granted FDA-approval for a clinical trial using 177-Lu to treat neuroendocrine tumors. At the Caring For Carcinoid Conference in Houston, Delpassand said the concept for PRRT began with a 65 year-old paper on radioactive iodine.

"This (radioactive iodine) is a sort of sliver bullet to kill thyroid cancer," he explained. The radioactive iodine is absorbed by the thyroid tumor but the rest of the isotope is cleared from the body. The isotope has a long residence time, meaning it stays in the body long enough to kill the cancer."

Delpassand then outlined the basics of commonly used medical isotopes:

Alpha particles – don’t travel through the body, contain high energy.

Beta – radioactive particles decay and can travel short distance in tissue.

Gamma – have long pathway and if you have a camera outside the body, you can capture an image of the particles as they travel through the body. This is characteristic of such imaging as bone scans and some other procedures.

The most commonly used agent is the Beta particle. It's the basis of the radioactive forms of Lutetium, Yttrium and also Indium. These isotopes also contain auger electrons (Auger pronounced O-zhay) which promote the penetration of the particulate and electromagnetic radiation. The result, often called the "crossfire effect," is the value of PRRT (peptide receptor radionuclide therapy.)

Another way of envisioning the effect is putting a bomb (isotope) in a car (somatostatin) and driving it into an area (tumor) where it detonates and pieces (particulate and radioactive "rays") fly in all directions, destroying the tumor by rupturing its cells.

Delpassand compared PRRT to other available treatments.

"Chemotherapy can reach an area with a good blood supply but if there's no blood going to the tumor, you can’t get the agent into the tumor. Radio-labeled agents (PRRT) go through the tissue and can reach ischemic or hypoxic cells." (Cells with very little oxygen or blood supply.)

The advantages and problems:

We can identify patients by small-dose "test drive" with octreoscan or the 68-gallium PET/CT. Delpassand says Excel plans to offer 68-Ga imaging in the "first half of 2012."

In addressing some problems with PRRT, Delpassand said protecting bone marrow is critical. "We have to gauge the dosemitry to make sure there's no damage to the marrow. In PRRT, it sometimes takes 4 to 6 weeks to know if bone marrow is damaged. We also have to protect the kidneys." Using positively-charged amino acid infusions can prevent the reabsorption of the radioactive materials into the kidney. Delpassand says he sees less than 1% of kidney damage PRRT in his practice.

If the tumor is limited to one organ and operable, surgery is the first line of treatment, he added. "Usually, we follow with octreotide. Somatostatin inhibits growth hormone and regulates hormone production." Octreotide, the manmade version of somatostatin, contains 8 amino acids, hence the "oct" for oct-reotide.

Excel has treated more than 100 patients with one of the three major isotopes (111-Indium, 177-Lutetium or 90-Yttrium) beginning in August 2005. Since 177-Lu has only been approved since January 2011, apparently most of these patients received 111-Indium.

Patient selection requires evidence of progressive disease, high uptake of the combo octreotide+ isotope, and certain blood characteristics, such as adequate platelet counts.

Variety of Protocols

There are three or four major protocols for administering PRRT. In Germany, Dr. Baum administers lower doses with longer waits between treatments. In Switzerland, patients get higher doses with less time (usually six week) between treatments. The Rotterdam protocol, which Excel employs, is very similar to the Basel protocol with treatment intervals of 6 to 9 weeks.

PRRT protocol also includes "carrier" variation. Some programs use the combination of octreotide, known as DOTA-TATE. Others use different carriers such as DOTA-NOC or DOTA-TYR.

One of the most debatable aspects of PRRT is which isotope to use. To date, there have been no randomized trials comparing the isotopes. Generally very small tumors may respond to 111-Indium although this isotope has not been used much lately in Europe. Indium has a very short path length, so it is unlikely to penetrate a tumor greater than 2 cm. But because of its shorter path, it also may do less damage to the marrow or kidneys. Early citations for Indium show relatively small does, Delpassand says. "Higher doses now are used," he added.

Lutetium is generally chosen for tumors 2.5 cm to 3 cm. Yttrium is thought to be more effective for tumors over 3 cm. Delpassand says Indium is safe for any tumor under 2 cm.

How do you know whether PRRT will help you?

Delpassand pointed to the following predictors: tumor histology, the extent of disease, tumor load, the type and number of earlier therapies, your score on the Karnofsky scale (ability to do normal activities,) whether there are liver mets and/or ascites. If the F-18 FDG PET is positive, that indicates a more aggressive tumor. Whether your tumor will absorb the radioisotope depends on your level of uptake (SUV) which can be determined from octreoscan. If your tumor shows on octreoscan, it will likely be at least partially affected by PRRT.

Delpassand says Lutetium and Yttrium both provide higher numbers of complete and partial response but he sees more stable disease with Indium, which also makes less renal and marrow toxicity. 90-Y, the stronger radioactive material also carries more toxicity, he adds.

PRRT is a targeted radioactive therapy, Delpassand says. "When we look at the literature, we see very few adverse reactions."

Health Insurance Coverage

A major drawback to PRRT has been lack of health insurance coverage for the costs. In the US. Delpassand says Indium usually is covered. He hopes to announce an agreement for insurance coverage for 177-Lu within a year.

"In the future, we need to treat at an earlier stage." he said. 

Q:What if you have a lot of liver tumors?"

"We have seen patients with more tha 80% occupation (liver displaced by tumor) but they may still have normal liver function, bilirubin levels, etc. If the patient's liver enzymes or bilirubin levels are less than 3 times normal, we can treat them."

It also may be possible to treat a patient who already had liver resection, a patient with only one lobe - it depends on whether the liver functions are normal. If these same conditions are teamed with abnormal liver functions, Delpassand says "we usually do not treat them."

Delpassand says at Excel, he works with a team of surgeons, interventional radiologists,oncologists, nuclear medicine specialists and people to help with reimbursement and scheduling.

The future of PRRT seems secure in Europe where they are now using combinations of the two lead isotopes, 177-Lu and 90-Y. Researchers in Poland and Australia are using tandem isotopes in NETs therapy.

For more information on Excel Diagnostics: exceldiagnostics.com