Fast neutron therapy utilizes high energy neutrons typically between 50 and 70 MeV to treat cancer.
Most fast neutron therapy beams are produced by reactors, cyclotrons
(d+Be) and linear accelerators. Neutron therapy is currently available
in Germany, Russia, South Africa and the United States. In the United
States, three treatment centers are operational in Seattle, Washington,
Detroit, Michigan and Batavia, Illinois. The Detroit and Seattle centers
use a cyclotron which produces a proton beam impinging upon a beryllium target; the Batavia center at Fermilab uses a proton linear accelerator.
Advantages
Radiation therapy
kills cancer cells in two ways depending on the effective energy of the
radiative source. The amount of energy deposited as the particles
traverse a section of tissue is referred to as the linear energy transfer
(LET). X-rays produce low LET radiation, and protons and neutrons
produce high LET radiation. Low LET radiation damages cells
predominantly through the generation of reactive oxygen species, see free radicals.
The neutron is uncharged and damages cells by direct effect on nuclear
structures. Malignant tumors tend to have low oxygen levels and thus can
be resistant to low LET radiation. This gives an advantage to neutrons
in certain situations. One advantage is a generally shorter treatment
cycle. To kill the same number of cancerous cells, neutrons require one
third the effective dose as protons.
Another advantage is the established ability of neutrons to better
treat some cancers, such as salivary gland, adenoid cystic carcinomas
and certain types of brain tumors, especially high-grade gliomas.
LET
Comparison of Low LET electrons and High LET electrons
When therapeutic energy X-rays (1 to 25 MeV) interact with cells in human tissue, they do so mainly by Compton interactions, and produce relatively high energy secondary electrons. These high energy electrons deposit their energy at about 1 keV/µm.
By comparison, the charged particles produced at a site of a neutron
interaction may deliver their energy at a rate of 30–80 keV/µm. The
amount of energy deposited as the particles traverse a section of tissue
is referred to as the linear energy transfer (LET). X-rays produce low
LET radiation, and neutrons produce high LET radiation.
Because the electrons produced from X-rays have high energy and
low LET, when they interact with a cell typically only a few ionizations
will occur. It is likely then that the low LET radiation will cause
only single strand breaks of the DNA helix. Single strand breaks of DNA
molecules can be readily repaired, and so the effect on the target cell
is not necessarily lethal. By contrast, the high LET charged particles
produced from neutron irradiation cause many ionizations as they
traverse a cell, and so double-strand breaks of the DNA molecule are
possible. DNA repair of double-strand breaks are much more difficult for a cell to repair, and more likely to lead to cell death.
DNA repair mechanisms are quite efficient,
and during a cell's lifetime many thousands of single strand DNA breaks
will be repaired. A sufficient dose of ionizing radiation, however,
delivers so many DNA breaks that it overwhelms the capability of the
cellular mechanisms to cope.
Heavy ion therapy (e.g. carbon ions) makes use of the similarly high LET of 12C6+ ions.
Because of the high LET, the relative radiation damage (relative biological effect or RBE) of fast neutrons is 4 times that of X-rays,
meaning 1 rad of fast neutrons is equal to 4 rads of X-rays. The RBE of
neutrons is also energy dependent, so neutron beams produced with
different energy spectra at different facilities will have different RBE
values.
Oxygen effect
The presence of oxygen in a cell acts as a radiosensitizer,
making the effects of the radiation more damaging. Tumor cells
typically have a lower oxygen content than normal tissue. This medical
condition is known as tumor hypoxia and therefore the oxygen effect acts to decrease the sensitivity of tumor tissue. The oxygen effect may be quantitatively described by the Oxygen Enhancement Ratio (OER). Generally it is believed that neutron irradiation overcomes the effect of tumor hypoxia, although there are counterarguments.
Clinical uses
The efficacy of neutron beams for use on prostate cancer has been shown through randomized trials.
Fast neutron therapy has been applied successfully against salivary gland tumors. Adenoid cystic carcinomas have also been treated.
Various other head and neck tumors have been examined.
Side effects
No
cancer therapy is without the risk of side effects. Neutron therapy is
a very powerful nuclear scalpel that has to be utilized with exquisite
care. For instance, some of the most remarkable cures it has been able
to achieve are with cancers of the head and neck. Many of these cancers
cannot effectively be treated with other therapies. However, neutron
damage to nearby vulnerable areas such as the brain and sensory neurons
can produce irreversible brain atrophy, blindness, etc. The risk of
these side effects can be greatly mitigated by several techniques, but
they cannot be totally eliminated. Moreover, some patients are more
susceptible to such side effects than others and this cannot be
predicted in advance. The patient ultimately must decide whether the
advantages of a possibly lasting cure outweigh the risks of this
treatment when faced with an otherwise incurable cancer.
Fast neutron centers
Several
centers around the world have used fast neutrons for treating cancer.
Due to lack of funding and support, at present only three are active in
the USA.
The University of Washington and the Gershenson Radiation Oncology
Center operate fast neutron therapy beams and both are equipped with a
Multi-Leaf Collimator (MLC) to shape the neutron beam.
University of Washington
The Radiation Oncology Department operates a proton cyclotron
that produces fast neutrons from directing 50.5MeV protons onto a
beryllium target.
The UW Cyclotron is equipped with a gantry mounted delivery system an
MLC to produce shaped fields. The UW Neutron system is referred to as
the Clinical Neutron Therapy System (CNTS).
The CNTS is typical of most neutron therapy systems. A large, well
shielded building is required to cut down on radiation exposure to the
general public and to house the necessary equipment.
Univ. of Washington CNTS
UW Cyclotron
Multi-Leaf Collimator (MLC) used to shape the neutron beam
Schematic of a treatment field delivery. The patient couch has been rotated, along with the gantry so the neutron beam will enter obliquely, to give maximum sparing of normal tissue.
Example of a treatment neutron field collimated using a neutron MLC
A beamline transports the proton beam from the cyclotron to a gantry
system. The gantry system contains magnets for deflecting and focusing
the proton beam onto the beryllium target. The end of the gantry system
is referred to as the head, and contains dosimetry
systems to measure the dose, along with the MLC and other beam shaping
devices. The advantage of having a beam transport and gantry are that
the cyclotron can remain stationary, and the radiation source can be
rotated around the patient. Along with varying the orientation of the
treatment couch which the patient is positioned on, variation of the
gantry position allows radiation to be directed from virtually any
angle, allowing sparing of normal tissue and maximum radiation dose to
the tumor.
During treatment, only the patient remains inside the treatment
room (called a vault) and the therapists will remotely control the
treatment, viewing the patient via video cameras. Each delivery of a set
neutron beam geometry is referred to as a treatment field or beam. The
treatment delivery is planned to deliver the radiation as effectively as
possible, and usually results in fields that conform to the shape of
the gross target, with any extension to cover microscopic disease.
Karmanos Cancer Center / Wayne State University
The
neutron therapy facility at the Gershenson Radiation Oncology Center at
Karmanos Cancer Center/Wayne State University (KCC/WSU) in Detroit
bears some similarities to the CNTS at the University of Washington, but
also has many unique characteristics. This unit was decommissioned in
2011.
MLC on KCC/WSU cyclotron
Schematic of MLC
Photo of the MLC
Schematic of the KCC/WSU gantry mounted superconducting cyclotron
While the CNTS accelerates protons, the KCC facility produces its
neutron beam by accelerating 48.5 MeV deuterons onto a beryllium target.
This method produces a neutron beam with depth dose characteristics
roughly similar to those of a 4 MV photon beam. The deuterons are
accelerated using a gantry mounted superconducting cyclotron (GMSCC),
eliminating the need for extra beam steering magnets and allowing the
neutron source to rotate a full 360° around the patient couch.
The KCC facility is also equipped with an MLC beam shaping device,
the only other neutron therapy center in the USA besides the CNTS. The
MLC at the KCC facility has been supplemented with treatment planning
software that allows for the implementation of Intensity Modulated
Neutron Radiotherapy (IMNRT), a recent advance in neutron beam therapy
which allows for more radiation dose to the targeted tumor site than 3-D
neutron therapy.
KCC/WSU has more experience than anyone in the world using
neutron therapy for prostate cancer, having treated nearly 1,000
patients during the past 10 years.
Fermilab / Northern Illinois University
The Fermilab neutron therapy center first treated patients in 1976,
and since that time has treated over 3,000 patients. In 2004, the
Northern Illinois University began managing the center. The neutrons
produced by the linear accelerator at Fermilab have the highest energies
available in the US and among the highest in the world
