Clinical development of positron emission tomography could be
hampered by an ongoing shortage of oxygen-18, the raw material
for a widely used PET tracer. The shortage is forcing PET researchers
to ration isotope supplies and cut back on studies just as third-party
reimbursement is opening the floodgates of clinical PET use.
"It's going to be a disaster if there's not another source
available to supply (oxygen-18) in the U.S. in the near future,"
said Dr. R. Edward Coleman, director of nuclear medicine at Duke
University Medical Center in Durham, NC. "The number of PET
centers is increasing rapidly and so is the amount of oxygen-18
needed by those PET centers."
Few PET researchers would disagree with Coleman about the seriousness
of the oxygen-18 shortage. Centers that need the isotope are being
put on a waiting list up to a year long, and often must cut back
on the amount they order.
The reasons for the shortage are more complex, however, and
touch on the larger issue of the federal government's role in
meeting the nation's demand for stable and radioactive isotopes.
That issue has sparked an ongoing feud between the U.S. Department
of Energy (DOE) and Isotec, a Miamisburg, OH-based firm that is
the only U.S. supplier of oxygen-18.
Oxygen-18 is a stable isotope that is the cyclotron target
material for fluorine-18, which in turn is the raw material for
18-fluorodeoxyglucose. FDG-18 is used in over 90% of clinical
Problems with oxygen-18 supplies began several years ago, after
the DOE closed down its Isotopes of Carbon, Oxygen and Nitrogen
(ICON) facility at Los Alamos National Laboratory in New Mexico
The ICON plant consisted of a distillation column sunk 500
feet deep into the ground. The column cryogenically distilled
nitrous oxide into oxygen-18-enriched water, which was then sent
to PET facilities around the country for refinement into fluorine-18
The DOE cited insufficient demand as the reason for its pullout,
which left Isotec and an Israeli company as the world's principal
oxygen-18 producers. Russia and China also have oxygen-18 facilities,
but until very recently did not export isotopes.
The oxygen-18 market did not become severely squeezed until
August 1990, when Iraq's invasion of Kuwait threw the Middle East
into turmoil and forced the Israelis to shut down their oxygen-18
plant, according to Vincent L. Avona, president of Isotec.
"You weren't getting any commercial freight planes flying
in that area of the world. Insurance rates were astronomical,
nobody was going to freight stuff in and out of the country,"
Avona told SCAN. "Nothing could move at all."
Isotec's share of the world's commercial oxygen-18 market surged
from one-third in 1989, when the DOE was still in the market,
to over 90% after the Israelis shut down. Given the increased
clinical interest in PET, the company simply did not have the
capacity to meet demand, Avona said.
The Israeli facility is now operating again, but has yet to
catch up with a daunting backlog of orders.
PET industry agitation for another source of oxygen-18 has
prompted the DOE to consider reentering the business, this time
by finding a private company to restart and operate the closed
ICON facility. But in another twist to the story, Isotec petitioned
to block the DOE from producing a number of isotopes, among them
oxygen-18. The company based its petition on federal Atomic Energy
Commission guidelines that discourage the government from competing
with private isotope suppliers.
The petition led to a running battle between the DOE and Isotec,
fought mostly in the pages of the Federal Register, where Isotec's
petition was published last year. Public comments solicited on
the issue reflected the anger of many clinicians upset at Isotec's
attempt to maintain a monopoly on a market it could not adequately
The DOE issued a final notice in June 1992 denying Isotec's
petition. The agency cited Isotec's difficulty in meeting demand
as the primary reason for its decision.
"The (public) comments note the past and current inability
and question the future ability of (Isotec)...to meet future demands
over time," the DOE stated. "DOE believes that its removal
from the actual or potential production and distribution of (isotopes)
could aggravate market instability."
For its part, Isotec maintains that it filed the petition in
an attempt to prevent the DOE from undercutting the substantial
investment the company has made in building new isotope production
plants. In addition, the company filed its petition almost a year
before the oxygen-18 shortage became critical. Because of bureaucratic
delays, the petition was published in the Federal Register during
the height of the shortage, according to Avona.
With Isotec's petition out of the way, the DOE's effort to
find a company to run the ICON plant has moved forward. Representatives
from several firms toured the facility this summer, and the DOE
is negotiating with one company that has expressed interest in
It would take about a year from the time a contract is signed
to get the ICON plant up and running, according to a DOE official.
The plant could double the supply of oxygen-18, the official said.
Isotec is also working to expand its capacity, according to
Avona. The company's third distillation column was completed this
summer and is now producing oxygen-18. Two more columns are being
built and will come on-line in late 1994.
The increased production capacity made possible by Isotec's
third distillation column is enabling the company to fill much
of the backlog of orders for oxygen-18. The shortage should begin
to ease by spring of 1993, according to Avona.
"We've been working very hard to eliminate the backlog,"
Avona said. "The wait should be reduced to just three or
four months, instead of a year."
Another company, Siemens' joint venture CTI PET Systems (CPS)
of Knoxville, TN, is developing a cyclotron add-on module that
will enable owners of Siemens cyclotrons to recycle oxygen-18-enriched
water. The module can recover between half and three-quarters
of the water used. It will be available on new Siemens cyclotrons
and as a retrofit to existing systems in January, according to
a company spokesperson.
A sister company of CPS, CTI Services, is working with foreign
isotope producers to import oxygen-18, the spokesperson said.
The oxygen-18 shortage is just one in a series of difficulties
nuclear medicine has experienced in maintaining a steady supply
of stable and radioactive isotopes. In many cases, those difficulties
are related to the DOE's gradual withdrawal from isotope production
over the past several decades as commercial suppliers enter the
market. As problems arise with conventional isotope stocks, the
DOE must scramble to find ways to meet demand.
In July, the world's supply of technetium-99m was nearly cut
off by a labor dispute at a Canadian nuclear reactor (SCAN 8/12/92).
The reactor produces the vast majority of molybdenum-99, the raw
material for technetium-99m.
The DOE is planning to restart a research reactor, also at
Los Alamos, to create a domestic source for molybdenum-99. DOE
officials expect to have the reactor producing molybdenum by April
The DOE has also been ordered by Congress to conduct a project
definition study for a National Biomedical Tracer Facility (see
story, page 3). The NBTF, which is being strongly promoted by
nuclear medicine specialists, would be dedicated to the production
of radiopharmaceuticals used in nuclear medicine.
Decisions by several third-party payers to reimburse for PET
scans have contributed to the increase in clinical usage of the
modality (SCAN 10/7/92). In addition, the Health Care Financing
Administration could approve Medicare reimbursement for PET early
next year, according to Michael McGehee of the Institute for Clinical
PET in Washington, DC. HCFA's action will most likely come after
a Food and Drug Administration ruling on FDG-18.
The FDA is in the final stages of its review of FDG-18, the
manufacture of which had first been regulated as part of the practice
of pharmacy. In May an FDA advisory panel found FDG-18 safe and
effective for evaluating suspected epilepsy, establishing myocardial
viability and localizing brain tumors (SCAN 7/1/92). Final FDA
action is expected by the end of the year.
The FDA and HCFA decisions will set off a surge in PET usage
that could strain production capacity even further.
"Next summer is going to be the most difficult time,"
McGehee said. "Medicare reimbursement will come in the spring,
and then we're looking not only at the purchase of machines, but
at the same time existing facilities will certainly increase their
volume as reimbursement is granted. That is going to stress the