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Aim to Kill
A big dose of radiation
isn't worth much if the tumor's not targeted properly, says
UNC radiation oncologist
By Jeannette Sabatini
illustration by Chris Capone
 If
it wants to find a better way to cure cancer, the radiation
oncology community needs to steer in another direction, says
Julian Rosenman, MD, PhD.
According to the professor
of radiation oncology at the University of North Carolina,
Chapel Hill, there are more successful avenues to curing cancer
than are being taken at present. For one, researchers should
be concentrating more on accurately targeting tumors than
on improving radiation dose delivery. Industry leaders, he
suggested, should consider the benefits of developing a scanner
that can provide a highly specific scan of a particular type
of tumor—a scanner that can perform with a spatial resolution
of 100 microns.
Likewise, computed tomography
(CT) scans, which are commonly used to plan radiation therapy
treatment, may not be the best choice for accurate treatment
planning, Dr. Rosenman tells ADVANCE. His provocative opinions
on radiation therapy were published in the January 2001 issue
of Radiation Oncology. "The recent technologic focus
of the radiation oncology community has been on the improvement
of radiation dose delivery," he writes. "The development
of intensity modulated radiation therapy [IMRT] has a high
priority in academic and industrial circles because it holds
the promise of delivering higher tumor dose and thus increasing
tumor control probability, for the same level of normal tissue
complication probability. But the value of high-quality IMRT
is completely negated if the tumor is improperly targeted."
Multimodality image-based
treatment planning
To better target the tumor, Dr. Rosenman encourages the employment
of multimodality image-based treatment planning. "New
imaging modalities, such as magnetic resonance spectroscopy
(MRS), positron emission tomography (PET) or functional imaging,
tuned to the particular tumor type, might reveal more than
just the gross tumor volume seen on CT or MR," he says.
"One could imagine radiation
treatment to many sites in the body under image guidance that
would result in cure of metastatic disease, should the cancer
be confined to a reasonable number of discrete sites."
At present, CT is often employed
as part of 3-D treatment planning, which is a tumor-based
approach. As part of this approach, the tumor is pinpointed
on a fully 3-D radiographic study that usually is constructed
with CT scans, Dr. Rosenman says. "In its full implementation,
such 3-D planning allows the radiation beam to enter at any
anatomically reasonable angle and radiation doses can be calculated
volumetrically."
But, Dr. Rosenman asks: What
if the tumor cannot be picked up on CT?
There are various reasons why
a tumor can be missed using CT, he says. For one, the planning
CT scan might be taken following surgery, when a tumor was
removed. The tumor also may have reduced in size as a result
of chemotherapy delivered prior to the taking of the treatment
planning scan.
"As we progress to more
sophisticated functional and tumor-specific imaging, the planning
CT may just assume the role of an anatomically correct 'backdrop'
for the information provided by these other scans," Dr.
Rosenman proposes. Additional data provided by other imaging
modalities could be added to or placed on top of the CT scan
in order to get a more specific determination of the location
of the tumor.
Yet, registering the CT scans
and the additional scans to combine the data from both is
very tricky, Dr. Rosenman says. The job becomes even more
challenging, he added, when data other than MRI or other CT
scans, such as functional imaging studies like PET, SPECT
or functional MRI are to be registered with the CT scans.
"The difficulties with
image registration are potentially more severe when one tries
to incorporate information from functional imaging studies
such as PET, SPECT, functional MRI or even newer techniques,
as these studies often have little anatomic information to
be used in the registration process," he explaines. "Imbedded
fiducial markers might solve the registration problem but,
in practice, it is likely that these scans will often be acquired
before the patient is referred to the radiation oncologist."
Intensity-based registration
To solve the registration problems, Dr. Rosenman sees the
need for the development of generalized methods of 3-D/3-D
registration. An approach to registration known as "intensity
based," which maximizes "mutual information"
may be best, he says.
"Intensity-based registration
relies on correlations between the color [gray scale] of pixels
in one image, and the corresponding pixels in the second image,"
he says. The less disorder in the registered images, the better
the registration.
"Registration on mutual
information does not require any pre-segmentation or division
of the image into anatomically meaningful parts. Indeed, registration
on mutual information requires no knowledge of the images
at all," he continues. "This means that it may be
very useful for functional images that do not show anatomic
boundaries well. Of course, we cannot know for certain how
to best apply mutual information technology until we have
actual experience with functional images."
To demonstrate how image-guided
radiation therapy may be done in the future, Dr. Rosenman
offers the case of a 70-year-old male who was 15 years post-I125
seed implant for an early stage prostate cancer. In this case,
a tumor that went undetected on CT was seen when the CT was
registered with a functional imaging study.
Dr. Rosenman says the patient's
PSA began to rise about seven years after his implant. Hormonal
therapy worked well until year 14, when the patient's PSA
climbed even higher than it had been seven years before. A
physical examination revealed a small, flat prostate with
one or two palpable iodine seeds.
A planning CT was registered
with a Prostascint™ scan that showed asymmetric uptake
in the right iliac chain. The CT had shown no tumor.
Based on the findings of the
nuclear medicine study, the patient was treated with an initial
field that encompassed the prostate and the tumor. A pelvic
field utilized was distinctly different from what would usually
have been used without the Prostacint™ registration.
At 4500 cGy, the treatment was changed to a boost field, and
the Prostacint™ positive area treated to 6000 cGy. Two
months after treatment, his PSA fell to undetectable levels
and remained so for a year.
"A functional image, tuned
to the particular tumor type, might reveal more than just
the gross tumor volume seen on CT or MR," Dr. Rosenman
says. "These images or studies could then be registered
to the planning CT scan and be used to guide therapy. Two
of the most promising approaches at present include PET and
MRSI."
Based on recent evidence, MRS
and other spectral analysis imaging techniques can reflect
tumor grade and malignant potential. "Radiation oncologists
could directly use this information to determine the clinical
target volume, which is an estimate of the volume of tissue
that harbors both microscopic and macroscopic tumor,"
Dr. Rosenman says.
Other Modalities Investigated
Molecular imaging and radiobiological phenotyping also are
being investigated to determine their application to multimodality
imaging. "As yet, these techniques have not been used
in radiation therapy treatment planning, but they hold the
potential for radically altering the way in which we treat
cancer," he reported.
Molecular imaging, he says,
may give an early indication as to the likely success or failure
of radiation or chemotherapy treatments. "Successive
changes in a particular molecular imaging modality during
treatment might indicate the relative ineffectiveness of a
specific chemotherapy combination or even a radiation fractionation
scheme, long before it became evident by traditional radiographic
methods."
Certain kinds of functional
imaging may indicate levels of acute radiation damage to normal
tissue. This, Dr. Rosenman says, may make it possible to perform
biologic in-vivo dosimetry.
Likewise, he believes it may
be possible, some day, to use functional imaging to determine
tumor control probability during the course of radiation treatment.
"Thus functional imaging might make it possible to stop
treatment in a patient-specific manner instead of just using
statistical methods as we do today."
Tumors also could be better
highlighted with the advent of scanners that could perform
at a higher resolution, say 100 microns, Dr. Rosenman suggests.
"It is interesting to speculate what might be accomplished
if a highly tumor-specific scan could be performed with a
spatial resolution of 100 microns (0.1 millimeter),"
he says, adding that mammography scanners already achieve
this goal, imaging microcalcifications of 100 microns or less.
"The average human cell
is approximately 10 microns in linear dimension, so a densely
packed sphere of 1000 malignant cells would have a diameter
of about 100 microns, and be detectable by our hypothetical
scanner," he continues. "What would a whole body
scan of a breast cancer patient with supposedly localized
disease show? Because we know that many such patients benefit
from adjuvant chemotherapy, it is clear that these patients
must have micro-metastatic disease somewhere in their body.
At the 100-micron level, would the disease be manifested as
a diffuse process throughout the entire body or as a countable
number of nodules that might be amenable to individual local
treatment?"
Once research has mastered
better localization of tumors, it should then concentrate
on dose delivery, Dr. Rosenman says. Researchers at the University
of California at San Francisco (UCSF) are already reaching
this goal.
At UCSF, researchers are using
MRS to determine the precise location of the prostate tumor.
Although still limited by spatial resolution, it allows these
workers to boost part of the prostate with safety.
"In [UCSF's] plan, IMRT
is used to treat intraprostatic disease defined by MRS to
90 Gy while treating the entire gland to 70 Gy," Dr.
Rosenman says.
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Aspirin May Help Prevent
Some Kinds of Cancer-Study
Sun Apr 7, 7:15 PM ET
By Deena Beasley
SAN FRANCISCO (Reuters) - Anti-inflammatory
drugs like low-dose aspirin, already used to protect against
heart disease, may help prevent some kinds of cancer in people
at high risk of developing the disease, researchers said on
Sunday.
"We've been focusing on
a cure for invasive cancer for several decades, but it's a
tough nut to crack. We've come to realize that cancer is like
heart disease or diabetes -- it takes 20 or 30 years to develop,"
Dr. Joyce O'Shaughnessy, co-director of breast cancer research
at Baylor-Sammons Cancer Center in Dallas, said at a meeting
of the American Association for Cancer Research.
People with precancerous conditions
-- like benign colon polyps -- have a 25 percent to 50 percent
chance of developing metastatic cancer, or cancer that spreads
to vital organs and is eventually fatal, she said.
"Pre-cancer is cancer
in evolution. Like high blood pressure or high cholesterol,
it should be treated early," said Dr. Gary Kelloff, senior
scientist at the National Cancer Institute .
Just five drugs are approved
by the U.S. Food and Drug Administration as cancer-prevention
treatments, including the breast cancer drug Tamoxifin and
the arthritis drug Celebrex, which was found to inhibit a
rare type of inherited colon cancer.
As a result, pre-cancer is
mainly treated with surgery -- cervical cells are removed
after an abnormal pap smear or colon polyps when they are
found by a colonoscopy, but surgery is not foolproof, can
be disfiguring and often has to be repeated, Kelloff said.
A three-year study of 1,121
people with benign colon tumors, called adenomas, showed that
a daily low-dose, or "baby," aspirin cut their risk
of developing more tumors by 19 percent, according to Dr.
John Baron, professor of medicine at Dartmouth Medical School
in Lebanon, New Hampshire, and an author of the study.
The risk reduction, compared
to patients on placebo, rose to 40 percent for participants
on the 80 mg baby aspirin who had a more aggressive type of
adenoma, he said.
The study also tracked patients
who took a regular, 325 mg, aspirin each day, but they showed
no significant benefit. It was not clear why the higher-dose
aspirin was less effective.
"Overall, there was a
significant reduction in the risk of new adenomas in people
taking baby aspirin. But it is clear that aspirin will not
be a magic bullet. It will have to be integrated into routine
care, supervised by a physician," Baron said, cautioning
that even in low doses aspirin can lead to side effects such
as bleeding and stroke.
He theorized that aspirin works
to curb colon tumors because it interferes with the COX-2
enzyme, which is associated with certain kinds of cancer cells.
As a result, the drug could have a similar anti-carcinogenic
effect in other gastrointestinal cancers such as esophageal
and stomach, Baron said.
Along with the COX-2 enzyme,
aspirin interferes with the stomach-protective COX-1 enzyme,
which means aspirin can cause gastrointestinal upset and bleeding.
A newer class of anti-inflammatory
drugs, including Pharmacia Corp.'s Celebrex and Merck's Vioxx,
that inhibit only the COX-2 enzyme, are also being studied
as pre-cancer treatments.
"Metabolically they are
half of an aspirin. Because they knock out COX-2 and not COX-1,
they should have the same effect as aspirin," Baron said.
Celebrex is now being studied
in clinical trials to see if it works to reduce pre-cancerous
conditions including benign colon polyps, Barrett's esophagus,
which is a precursor to esophageal cancer, pre-skin cancer
and a type of bladder cancer, according to Pharmacia.
Gene Tied to Deadly Prostate
Cancer
Wed Oct 9, 2:19 PM ET
By MARK EVANS, Associated Press Writer
Scientists say they have found
a gene that predicts whether prostate cancer will develop
into its most lethal form — a finding that could someday
help doctors decide how to treat men with the disease in its
early stages.
Some prostate tumors remain
confined to the prostate, some spread to other parts of the
body. But doctors have no way to know before the cancer actually
spreads. The aggressive, metastatic form kills more than 30,000
American men each year.
In their study, University
of Michigan Medical School researchers examined tumor cells
taken from prostate cancer patients. They found 55 genes that
were more active in metastatic cells than in less-lethal cells.
A gene called EZH2 was the most active of all.
They found that the intensity
of EZH2's activity increased as the disease progressed. And
patients who showed higher levels of the EZH2 protein were
more likely to get the deadlier form of the disease.
"It suggests that this
is a lethal biomarker, that it portends aggressiveness,"
said Arul M. Chinnaiyan, an assistant professor of pathology.
The findings were published Thursday in the journal Nature.
Chinnaiyan said that if a test
can be developed, EZH2 protein levels could be used to decide
which patients need aggressive treatment, including radiation
or surgery.
A recent study found that many
men over 60 receive unnecessary surgery and other treatments
for prostate cancer that is unlikely to spread. Prostate surgery
can cause impotence and urinary incontinence.
Doctors now have several methods
of diagnosing prostate cancer, including a test that measures
the level of a prostate-specific antigen in the blood. The
researchers said the prevalence of EZH2 in the tumor cell
is a more accurate predictor of a patient's survival than
the PSA level.
The gene's exact role in tumor
development remains unclear. But the researchers speculated
that EZH2 may suppress genes that slow the spread of the disease.
"It's just a piece of
the puzzle, and there are going to be a lot of little pieces
like this in coming years," said Thomas Wheeler, a pathology
professor at Baylor University College of Medicine. "But
this gene does seem to be important over the whole spectrum
of prostate cancer."
Prostate cancer is the second-deadliest
form of cancer among American men, behind lung cancer. Roughly
189,000 Americans are diagnosed with the disease each year.
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