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Total-Body Irradiation for Bone Marrow Transplantation

Total-Body Irradiation for Bone Marrow Transplantation

Total-body irradiation (TBI), when given as
part of bone marrow transplantation (BMT), works by enhancing immune
suppression and by exerting a tumoricidal effect. The modality has
been made less toxic because of new approaches to delivering TBI,
such as fractionation, and partial organ shielding, Colleen Lawton,
MD, professor at the Medical College of Wisconsin, Milwaukee, said at
the 1998 American Society for Therapeutic Radiology and Oncology meeting.

Total-body irradiation has continued to play a pivotal role in the
conditioning regimens for BMT, which has become a common modality in
the treatment of both acute and chronic leukemias and myelodysplastic
disorders, as well as relapsed Hodgkin’s and non-Hodgkin’s
lymphomas. Transplantation is also gaining favor in the treatment of
aggressive multiple myeloma, breast cancer (autologous
transplantation), neuroblastoma, Ewing’s sarcoma, and relapsed
testicular carcinoma. In addition, BMT has a role in benign but fatal
diseases, such as refractory aplastic anemia, some congenital
deficiency disorders, and, xperimentally, in some autoimmune disorders.

Stem-cell transplantation also looks promising in the treatment of
primary progressive multiple sclerosis (MS). Patients qualifying for
the experimental protocols are bed-bound and likely to die of their
disease within 2 years. In half a dozen or so patients who have
received this therapy, disease status has substantially improved and
lesions have regressed, as measured on magnetic resonance imaging
(MRI). In laboratory models of an MS-like syndrome, TBI prior to
transplantation decreases the likelihood of disease progression to a
greater extent than does transplantation without TBI. Therefore, TBI
may have an adjunctive role in this new approach, Dr. Lawton predicted.

The closer the donor-recipient match in terms of HLA antigens, the
lower the transplant-related mortality. Therefore, HLA-matched
sibling donors offer the best chance for success. Unfortunately, only
25% to 30% of patients have an ideal match. Therefore, there is a
heavy reliance on partially matched, related donors and unrelated,
matched donors. The National Marrow Donor Program has greatly
facilitated the pairing of patients with nonrelated, matched donors,
offering Caucasians a 30% to 40% chance of locating an HLA-identical
unrelated donor. However, non-Caucasians have a much poorer chance of
finding a matched donor, and there is a great need for donors from
all non-Caucasian races to help remedy this problem.

More Effective, Less Toxic TBI Regimens

Advances have been made in rendering TBI more effective and less
toxic through greater understanding of marrow recovery. Even when
large amounts of marrow are exposed to high doses of radiation,
marrow recovery can occur as long as significant portions of the
marrow have been shielded. In breast cancer patients, Sykes and
colleagues showed that 30 Gy, delivered at 2 Gy per fraction, seemed
to be the tolerance beyond which marrow regeneration did not
occur.[1] At or above a radiation dose of 30 Gy, 50 (96%) of 56
sternal biopsies showed little or no marrow regeneration.

The response of the peripheral blood cells days after irradiation
varies, depending on cell type. Lymphocytes, being the most sensitive
cells in the peripheral blood, clearly diminish shortly after the
delivery of the TBI. The effect on granulocytes is seen after 1 to 2
days, with regeneration in 20 to 24 days. Platelet effects are seen
after 2 to 3 days, with regeneration in 14 to 21 days. The least
sensitive cells, the erythrocytes, recover the fastest. The magnitude
of the respective cytopenias depends not only on the radiation dose
but also on the normal lifespan of the respective circulating cell
and its inherent sensitivity to radiation, Dr. Lawton pointed out.

Several lines of evidence support a total dose/fractionation
relationship in TBI, especially in T-cell–depleted, unrelated,
or mismatched donor transplants. Data show that increasing doses of
TBI correlate with increased engraftment, that a single dose of TBI
is more immunosuppressive than the same total dose conventionally
fractionated, and that bone marrow myeloid eradication is greater
with hyperfractionation (with the total dose slightly increased over
a single dose).

In humans receiving a non–T-cell–depleted allogeneic
transplant from a matched sibling, it has been fairly well
demonstrated that no one TBI regimen produces more favorable
engraftment rates, because engraftment is virtually 100% for these
types of patients. However, with more difficult grafts, both animal
and human studies have shown that with increasing TBI dose or with
the addition of total lymphoid irradiation (to increase immune
suppression) to standard TBI, engraftment rates improve. This may
occur because the lymphocytes have a “very small shoulder”
on the cell survival curve, meaning that their likelihood of repair,
even with fractionation, is small. The same is true for leukemic or
other cells targeted for killing. Fractionation, therefore, should be
beneficial, Dr. Lawton said.

Compared with single-dose irradiation, fractionation also appears to
be less toxic to normal tissues, which are also affected by TBI at
some level, with the lung being the principal dose-limiting organ of
concern. Multiple clinical regimens have supported this notion, and
to date, dramatic sparing of the lung and intestines has been shown
with more fractionated regimens, she said.

Commonly Used TBI Schedules

In the first published description of a dedicated TBI unit in North
America, the patient was placed in a room with a radiation source and
a canary was placed in a cage near the patient. Death of the canary
during the delivery of the radiation was a signal to discontinue the
radiation. Considerable advances since that time have made TBI much safer.

The most commonly used TBI schedule in the United States is 1,200 cGy
in six fractions, delivered either once or twice daily, without
shielding. “But if you are doing T-cell–depleted
transplants or transplants from mismatched or unrelated donors, data
from multiple centers would suggest that 12 Gy in six fractions is
not enough,” Dr. Lawton said.

In a small series from the Fred Hutchinson Center in Seattle, 20
patients with matched donors were studied, 11 of whom received 1,200
cGy in six fractions (the standard dose) and 19 of whom received
1,575 cGy at 225 cGy per fraction. Engraftment was unsuccessful in 6
of the 11 patients treated with the 1,200 cGy in six fractions. As
the TBI dose increased, nonengraftment was decreased, presumably
because immunosuppression was enhanced.

“When you don’t get a graft in, the patient usually dies.
And the likelihood of getting a successful second graft in is small.
It’s exceedingly important that you get the initial graft
in,” Dr. Lawton stressed.

In a similar situation with T-cell–depleted transplants,
Memorial Sloan-Kettering researchers also found that 20 of 22 matched
transplants were successfully engrafted, compared to only 10 of 20
mismatched transplants. The dose of radiation used in this study was
1,320 cGy. The authors concluded that a more intensive preparatory
regimen is needed to achieve engraftment. One way to do so, according
to Dr. Lawton, is to increase the TBI dose.

“So although the most common schedule is 12 Gy in six fractions,
there are indications for higher doses, especially in unrelated or
mismatched transplants where you may need increased immune
suppression. You can get increased immune suppression from the TBI,
and this will help the graft to take,” she said. Use of
hyperfractionated TBI to doses above 12 Gy (ie, 13.50 to 14 Gy) is
one way to successfully increase engraftment rates for these
unrelated or mismatched transplants.

In terms of positioning the patient for TBI, no one method has proved
to be superior. However, with what-ever position is chosen, there
should be + 10% dose homogeneity, Dr. Lawton said. This means, that,
in general, the anterior/posterior-posterior/anterior (AP/PA)
technique is preferred over the lateral technique. A range of beam
energies are acceptable, as long as beam spoiling of the
higher-energy beams is performed to ensure that the dose to the skin
surface is delivered as prescribed.

Toxicity

The principal dose-limiting organ of TBI is the lung. Interstitial
pneumonitis from TBI remains a problem for patients who undergo
transplantation because it accounts for approximately 40% of
transplant-related deaths. Early studies found that the occurrence of
pneumonitis was related to the dose rate of TBI, and that very low
dose rates—on the order of < 2 cGy/min—were necessary to
avoid this side effect. However, numerous investigators have since
shown that higher dose rates and total doses can be safely delivered,
as long as they are fractionated.

In fact, the development of hyperfractionated TBI was based on the
hypothesis that one could decrease the incidence of pneumonitis while
increasing the dose to achieve a higher engraftment rate. By
escalating the dose of TBI, the engraftment rate was unquestionably
improved; however, mortality in patients who received higher TBI
doses without partial lung shielding was increased, mostly due to
lung toxicity.

“Today, with selective organ shielding, we can go to
significantly higher TBI doses than we ever thought we could without
it,” Dr. Lawton said.

Other Uses of Irradiation During the Transplant Process

Irradiation has a number of other uses during the transplant process:
treating splenomegaly, treating the central nervous system (CNS),
boosting of local disease, and boosting of known or potential
testicular disease. In the treatment of splenomegaly, radiation is
used most commonly in patients with chronic myelogenous leukemia
(CML) as a means of avoiding surgery. Data from a European randomized
trial of CML patients who were given 10 Gy over 3 days initially
showed no improvement in disease-free survival. (There was often a
delay between the spleen irradiation and the conditioning regimen,
which is problematic, Dr. Lawton pointed out.) However, an updated
analysis of this study identified an intermediate group of patients
who actually benefited from spleen irradiation, such that the relapse
rate at 8 years was 8% with splenic radiotherapy and 30% withoutit.

“So I think there is still a role for splenic irradiation,”
Dr. Lawton said. “At our institution, if you have mild
splenomegaly, you do get radiation as a boost prior to TBI, but if
the splenomegaly is more prominent we generally take the spleen out surgically.”

A radiation boost to localized disease is often used in patients with
leukemias and lymphomas who have bulk disease, and also in patients
receiving solid tumor transplants. The recommended dose is based on
tumor type, but is generally 10 Gy at 2 Gy per fraction for leukemias
and lymphomas when boosting is done in conjunction with TBI.

Administering radiation boosts to the testicles remains
controversial; however, data from Memorial Sloan-Kettering support
the use of a 4-Gy boost to the testicles in addition to TBI, based on
the occurrence of relapses in 4 of 28 patients who received no boost
to the testicles, compared with 0 of 600 who had the boost.

“This testicular boosting is done to decrease the risk of
testicular relapse in patients with leukemia. At our institution we
don’t routinely use it, although we certainly will do it in
patients who are on a protocol requiring testicular boosting.
It’s clearly controversial; nevertheless, you can’t ignore
the data from Memorial Sloan-Kettering,” Dr. Lawton commented.

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