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June 2010 - December 2013
III - ALTERNATIVE BREAST CANCER SCREENING TESTS
3. Poor alternatives to standard mammography
In addition to the X-ray tests - conventional mammography, either film or digital, dedicated breast CT and breast tomosynthesis - there are imaging techniques based on other forms of ionizing radiation that can be used for breast examination. At present, medical diagnostic uses gamma-ray imaging and positron emission tomography (PET).
These technologies offer generally higher imaging quality than the standard mammography. However, they generally deliver significantly higher dose of ionizing radiation, hence also come with the higher risk of causing what they should help fight - breast cancer, but also other cancer forms as well.
Gamma-ray imaging and PET are part of so called nuclear medicine.
Diagnostic gamma-ray imaging uses techniques based on the radioactive gamma rays produced by radionuclides (radioactive isotopes) injected into the bloodstream. Isotope, either alone, or chemically combined with compounds that enhance its concentration in the specific organ and/or malignant cells, are absorbed by body tissues in different concentrations. Hence radiation they emit can be used to create an image of the body tissues by one or more gamma cameras, capturing the radiation.
Unlike X-ray imaging techniques, which primarily detect pathologic (physical) tissue changes, gamma imaging also can target and detect tissue cells with the forms of altered metabolism indicating malignant growth. For that reason, gamma imaging can detect some cancers not visible in X-ray mammography, and also has the potential for better differentiation of malignant vs. benign growth. However, due to its technological limitation, it was less efficient in detecting small tumors (less than about 1 cm), important for early diagnosis.
This limitation applies to the oldest form of gamma imaging, scintimammography (also called Miraluma, or sestamibi imaging, for the radioactive compound it uses, Miraluma Tc-99m sestamibi), introduced to medical imaging in the mid-to-late 1990s. Similarly to the CT technology, adapting early gamma-ray imaging apparatus to the specific breast-imaging application, in this case by replacing a large, general-use gamma camera with a smaller one, closer to the breast, significantly improved imaging quality.
The two scintimammography technologies optimized for breast imaging are Breast-Specific Gamma Imaging (BSGI, by Dilon Technologies) and Molecular Breast Imaging (MBI, by GammaMedica). The former uses single small gamma-camera ("dedicated breast gamma camera") with advanced detector; reportedly, it is capable of detecting tumors down to 1mm in size. The later, which uses similar dual-head gamma camera and a different detector can, according to the manufacturer, detect tumors down to 3mm.
However, both technologies still struggle with another drawback of scintimammography:
significantly higher radiation exposure
than with the X-ray mammography. This time, it is not only the breasts that are exposed to radiation, but the rest of the body as well.
The facts on radiation exposure during medical diagnostic procedures are quite commonly poorly presented, misrepresented or misunderstood. And more so when it comes to the exposures to gamma radiation from injected radioactive isotopes. Despite the clear official stance that the effective dose shouldn't be used for an assessment of the individual radiation risk, it is the form in which radiation exposures here are routinely presented.
Table below shows radiation exposure of the human body resulting
from injection of two different forms of the most commonly used
radioactive tracer in gamma imaging, Technecium-99: SestaMIBI (Miraluma,
commercially available as Cardiolite)
and Tetrofosmin (commercially available as Myoview). Both are used for myocardial perfusion, with
the former also being the radiopharmaceutical of choice for
gamma-ray breast imaging (the reason is obvious, since its
estimated breast concentration is nearly four times higher than
Approximate value based on ICRP cumulative value
for 14 tissues and/or organs ("remainder tissues", which in addition to those listed
in the table include extrathoracic region, lymphatic nodes,
oral mucosa, prostate, and cervix)
The above radiation doses are based on the published data of an international study sponsored by the European Association for Nuclear Medicine (Bombardieri et al. 2003). The overall radiation dose is more than double that given with the official U.S. prescriptions, mainly due to the larger number of organs included (25 organs plus a sum for the remaining organs in the study vs. 16 organs in the standard U.S. prescription data). Methods of dose estimation also may differ, with the study being based on ICRP 80 (issued in 1998), while the U.S. dose estimation seem to be based on methods dating from 1975, possibly even 1968.
Of particular interest is breast irradiation. The effective breast dose of 0.0456 mSv per 100 MBq is two and a half times higher than that quoted in U.S. prescriptions. Since the study uses more recent dosimetry data, and is focused on the use of these two radiopharmaceuticals for breast imaging (U.S. prescriptions are primarily for cardio/pulmonary imaging), its estimated dose should be be more accurate.
With the standard injection dose of Tc99 sestaMIBI being 740-1110 MBq (20-30 mCi in older units of millicuries), estimated dose of radiation absorbed by the breasts is in the 2.8-4.2 mSv range, with the corresponding effective dose 0.34-0.51 mSv. Nominally, it is roughly almost twice lower than the average radiation dose from X-ray mammography (about 6 mSv absorbed dose). However,
breast irradiation here is only a small fraction
As the table indicates, the whole body effective radiation dose with gamma-ray imaging is about 20 times higher than for the breasts alone. Hence, radiation exposure is about 10 times higher than with the standard average X-ray mammography. While the risk of developing breast cancer is nearly cut in half with gamma-ray imaging, the risk of developing any cancer due to injected radioisotope is
nearly ten times higher.
This assumes that the radiation weighting factor for both, high-energy gamma-rays (140 KeV) and low-energy X-rays (20-25 KeV) is the same, officially set to 1. As mentioned before, there is a very suggestive evidence that high-energy ionizing radiation inflicts less biological damage. In light of it, it is likely that the actual risk with gamma-imaging is significantly lower; possibly, only half as high as the official dosimetry implies. Still, the risk of any cancer with it would be up to several times higher than the risk of breast cancer with mammography.
In addition, injected radiopharmaceuticals also cause frequent side effects.
That, however, may be changing for the better. Relatively recent technological advances made possible significant radiation dose reduction with gamma-ray breast imaging. The two frontrunners at the moment, as mentined, are so called Molecular Breast Imaging (MBI, GammaMedica) and Breast-Specific Gamma Imaging (BSGI, Dilon Technologies), both offering image quality significantly improved over the standard scintimammography.
While both started out with the standard recommended dose of 740-1110 MBq of Te99, GammaMedica reports that recent trials with improved collimator and somewhat lower energy radiopharmaceutical used several times lower radiation dose, while maintaining the same level of image quality. Specifically, the low-dose MBI requires only 148 MBq. That translates into as little as 0.6 mSv and 0.07 mSv absorbed and effective dose for the breasts.
The effective whole-body dose is about 1.3 mSv - still two to three times higher than with the standard X-ray mammography (using identical radiation weighting factor; as mentioned above, the actual effective dose with gamma-radiation is probably nearly half as high as with low-energy X-rays). GammaMedica and its researchers at Mayo clinic hope they could further reduce the radiation dose, by about a half, to 76 MBq. That would nearly equate the risk of developing any cancer due to injected pharmaceutical to that of developing breast cancer due to mammography X-rays.
It would make MBI a direct alternative for screening asymptomatic women. MBI's advantage would be generally better accuracy in breast cancer detection, but that comes at a price: projected average reimbursement per scan is $450, about twice that for mammography.
The third nuclear medicine breast imaging technology, Positron Emission Mammography (PEM), is not a candidate for breast cancer screening technology. But it is used fairly regularly for breast cancer diagnostic, so it warrants brief coverage.
Positron emission tomography (PET) is a 3-D imaging technology dating back to the 1970s. Together with other gamma-ray imaging technologies, it belongs to so called nuclear medicine. Its distinction is in the way that gamma radiation is produced. While other gamma-ray technologies use radioactive isotopes directly emitting gamma-rays, PET uses proton-rich isotopes - for cancer imaging, it is commonly fluoro-deoxy-glucose (usually abbreviated FDG, radiopharmaceutical combining glucose and radioactive isotope fluorine-18 - which stabilizes by decaying protons into neutron, neutrino and a positron (in effect, a positively charged electron).
The ejected positron travels an average 2-3 mm before it loses enough energy to be able to interact with a body electron. The two annihilate, transforming into two gamma-ray photons emitted in opposite directions.
Gamma-ray radiation produced by annihilation is than detected by a gamma camera. Since FDG binds glucose molecule, it gets absorbed at a higher rate by glucose-hungry cancerous cells. This makes them visible on gamma-ray image as denser spots of more intense gamma-ray emission.
In addition to malignant growth, PET FDG imaging is particularly effective in diagnosing neurological (where the activity of brain cells affects their glucose intake) and cardiac (where blood-starved portions of the heart muscle get and use less glucose) disorders.
As the other forms of imaging using injected radiotracer, PET's detection of cancerous growth is based on the anomalous metabolism of cancer cells. That generally results in a higher level of accuracy in discriminating between benign structural tissue abnormalities and an actual malignant cancer.
However, the standard whole-body PET scanner, similarly to the whole-body CT, lacks in resolution, which is very important aspect in the early detection of breast cancer.
To remedy that, breast-dedicated positron-emission scanner is designed to use smaller gamma cameras that can come very close to the breast tissue, only separated from it by the holding plates for immobilizing the breast. This significantly improved resolution, by reducing signal noise, while also requires lower dose of the radioactive tracer. This specialized form of PAT became PAM - positron emission mammography.
With the potential to detect cancers of only 2-3mm in size, PEM resolution level compares to that of other two major forms of gamma imaging, BSGI and BMI. However, it is more expensive, and delivers about as much radiation to the patient as these other two breast-specific gamma-ray modalities - which is significantly more than with the standard X-ray mammography (this does not include GammaMedica's still experimental low-dose MBI).
According to a recent study that compared radiation dose
delivered by PEM and BSGI to that delivered with the standard
film and digital
In comparison, the effective doses for the standard 2-view (per breast) film and digital X-ray mammography came at 0.44 and 0.56 mSv, respectively.
If so, cancer risk due to radiation exposure would be anywhere
from about dozen to over 20 times higher with BSGI and PEM,
than with the standard mammography. Hendrick, however, based his comparisons not on the effective dose, but on BEIR VII mortality rates for the absorbed dose. That gives somewhat higher risk - up to 30 times for BSGI and PEM versus mammography.
The study did not include recent developments in the nuclear medicine, such as above mentioned significant reduction in radiation dose with the BMI breast gamma-ray imaging reported by GammaMedica. On the other hand, hopeful beginnings do not always pass the final test: a few years ago, Naviscan - the manufacturer of the first FDA approved PEM imaging scanner - was indicating that use of a new, B12-bound radiopharmaceutical could dramatically reduce patients radiation exposure with their PEM-Flex. That never materialized.
But one thing is certain: as the radiation risk factor becomes real public concern, and as the unfavorable risks-to-benefits ratio of the standard X-ray mammography are becoming more clearly defined, there is a need - and a huge marketing niche - for the effective, low-risk alternative test suitable for breast cancer screening. At present, nuclear medicine is far from passing the radiation exposure hurdle. But things could change, and could change fast.
Its possible ace-in-the-sleeve is the probably inaccurate official assessment of the cancer risk in the radiation range from low-energy X-rays to high energy gamma-rays. At present, they are all assigned the same radiation weighting factor, 1; a good bit of evidence, however, suggests that the actual gene-damaging potential at the low-energy end is roughly double that at the high-energy end of the range. So gamma-ray mammography operating at 140 keV, and PEM operating at 511 keV (vs. X-ray mammography operating at about 25 keV.) have a realistic chance for their radiation risk to be officially cut up to 50%, or somewhat more, on that basis.
This overview of the alternative tests to the standard mammography also using ionizing radiation - either X-rays or gamma-rays - does not offer a clearly better solution. Some test are better in some aspects, worse in the others. Those that remain at an acceptable radiation level cannot significantly improve the main problem of standard mammography:
insufficient accuracy in indicating which abnormal growth is actually a malignancy.
Without it, most of the benefit of early diagnosis morphs into the negative of overdiagnosis and overtreatment, with the problem of false positives remaining, and with questionable benefit in reducing morbidity and mortality.
Do the alternative tests not using ionizing radiation compete better in this respect? Will find the answer on the following page.