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 Hodgkins and non-Hodgkins lymphomas. Transplantation is also gaining favor in the treatment of aggressive multiple myeloma, breast cancer (autologous transplantation), neuroblastoma, Ewings 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. 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-celldepleted, 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 nonT-celldepleted 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-celldepleted 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 dont get a graft in, the patient usually dies. And the likelihood of getting a successful second graft in is small. Its exceedingly important that you get the initial graft in, Dr. Lawton stressed.
In a similar situation with T-celldepleted 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.
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 rateson the order of < 2 cGy/minwere 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 dont routinely use it, although we certainly will do it in patients who are on a protocol requiring testicular boosting. Its clearly controversial; nevertheless, you cant ignore the data from Memorial Sloan-Kettering, Dr. Lawton commented.