Total Body Irradiation

R4洪逸平

Bone Marrow Transplantation (2011) 46, 475–484Best Practice & Research Clinical haematology (2007). 295-310

Current Opinion in Hematology 2008, 15:555–560

財團法人台灣癌症臨床研究發展基金會

Total Body Irradiation

The first examples of human surviving supralethal TBI in leukemia with BM infusion and grafting was in 1965 Cancer Res 1965; 25: 1525–1531.

Goals of TBI

Eradicating diseased marrow Reducing tumor burden Immunosupressive TBI may be particularly important in the

setting of matched-unrelated donor transplants, when adequate immunosuppression is essential

Deplete the BM to allow physical space for engraftment of healthy donor marrow

Total Body Irradiation

Dual opposing 60Co Advantages: highly homogenous radiation

exposure which allows the patient some freedom of movement

Disadvantages: cost, difficulties in organ shielding, and the problem of delivering higher dose rates

Linear accelerators a higher dose rate as well as organ shielding can

easily be administered. Major concerns: the dose rate, the fractioning

and the total dose

Dose, fractionation and dose rate employed during TBI

Myeloablative regimens

Early-myeloablative TBI regimens used single, large fractions of 8–10 Gray (Gy)

High risk of death from interstitial pneumonitis Fractionation and reduction od dose Dose rates <10–12 cGy/min are associated

with reduced rates of pneumonitis, nausea and vomiting

TBI in daily or twice-daily fractions appears to improve the therapeutic ratio, allowing higher radiation doses

inconvenient

Dose rate

Most of the clinically used TBI regimens the radiation is given at low dose rates (5 – 8 cGy/min)

High dose rates (60 – 80 cGy/min) in canine models showed more GI and marrow toxicity with more intense immunosuppressive effect

High dose rate increases the risk of interstitial pneumonitis and cataract

If TBI was fractioned, the toxicity reduced. Lower dose rates permitted higher total

doses

Fractionating Fractionating was applied to increase the

irradiation dose The total dose of fractionated TBI needs to be

increased to have a similar Immunosuppressive effect as single-dose TBI

Risk for late organ toxicity decreased and long-term survival improved in animal model

In clinical trials, Fractionated TBI showed less veno-occlusive disease (VOD) of the liver, a trend for fewer relapses and improved survival.

International Journal of Radiation Oncology, Biology, Physics 1988; 15: 647e653.

Journal of Clinical Oncology 2000

Bone Marrow Transplantation 1986; 1: 151-157

Dose, fractionation and dose rate in Myeloablative TBI

In the latter half of 20th century, myeloablative regimens delivering 12 Gy, twice daily, over 3 days, in combination with chemotherapy were most commonly employed

15-16Gy showed no improvement of OS (may be due to increased mortality unrelated to relapse)

Blood 1990; 76: 1867-1871

Blood 1991; 77: 1660-1665

Reduced-intensity conditioning regimens

In the 1990s, feasibility of reduced-intensity conditioning (RIC) regimens consisting of lower-dose TBI and/or fludarabine

Cytotoxic effect from such regimens is minimal – tumor cell death is largely dependent on a graft vs tumor effect

McSweeney et al. employing 2 Gy delivered as a single dose, with or without fludarabine, with cyclosporine and mycophenolate mofetil as GVHD prophylaxis in older patients

Other group use 2 Gy, single-dose, low-dose rate (7 cGy/min) TBI in the setting of both related and unrelated donor transplantation

Blood 2001; 97: 3390–3400

Blood 2004; 104: 961–968.Blood 2003; 102: 756–762

J Clin Oncol 2005; 23: 1993–2003.

Reduced-intensity conditioning regimens

Kahl et al. found better relapse free survival in CLL, MM, non-Hodgkin’s lymphoma patients

Graft rejection risk is higher in CML and MDS patients

Marks et al. compared cohorts of patients receiving myeloablative therapy vs RIC in ALL and showed no difference in mortality. However relapse rate increased in RIC group

Biol Blood Marrow Transplant 2005; 11: 272–279.

Blood 2007; 110: 2744–2748.

Morbidity associated with current regimens for TBI

interstitial pneumonitis In ~50% if single, large fraction of 8-10

Gy, with 50% fatal 25% in fractioned and low-dose-rate TBI CMV infection may take a role

Acute toxicities associated with TBI

Nausea and vomiting Preventable with modern anti-emetic

agents Parotitis

Occur after the first 1-2 fractions, subsided within 1 – 2 days

Unique to TBI Dry mouth and mucositis

5 – 10 days after TBI

End-organ damage and late effects after TBI

Cataract Gonadal failure Thyroid dysfunction Kidney dysfunction Decreased bone mineral density Xerostomia Short stature and endocrine dysfunction in child Increased risk for cardiometabolic traits, including

central adiposity, hypertension, insulin resistance and full-blown metabolic syndrome

Venoocclusive disease of the liver may occur in 10–70% of patients

Second malignant neoplasms

Two large, recent, analyses demonstrated the risk of solid tumor after BMT to range from 3 to 7% at 15 years following transplant

A recent multi-institutional analysis of 28 874 allogeneic transplant recipients allogeneic transplant recipients demonstrated a 3.3% incidence of development of a solid tumor 20 years

This risk was increased for the 67% of patients who received irradiation compared with those who did not

This excess risk was observed only in patients who received radiation ≦ 30 years old

Curtis et al. 58 observed the risk of solid tumor to be 2.2% 10 years after BMT, and 6.7% 15 years

Blood 2009; 113: 1175–1183.

N Engl J Med. 1997; 336 (13): 897–904.

Second malignant neoplasms

Radiotherapy was observed to increase the risk of second cancers, this risk is significantly higher in receiving >10 Gy than <10Gy

Patients are also at risk for further hematological malignancies, including MDS and AML

J Clin Oncol 2000; 18: 348–357.

Protection of normal tissue during TBI

Physical blocks TLI for immunosuppression during BMT

TLI may result in increased proportions of natural killer T cells Prevent GVHD by inhibit conventional T cell

Lowsky et al. described 37 patients with lymphoid malignancies or acute leukemia treated with 800 cGy total TLI, over 10 fractions, 3% ≧grade II GVHD with increased odds of early CMV viremia

Future directions: increased conformality and potential for dose escalation

Potential use of helical tomotherapy Potential use of proton beam

radiotherapy Potential use of radioimmunotherapy

ALL The most commonly used regimen for

transplantation of patients with ALL is CY plus TBI

Retrospective analysis from the IBMTR found that a conventional CY/TBI regimen was superior to a non- TBI-containing regimen of BU plus CY, with a 3-year survival of 55 versus 40% for BU/CY. With similar relapse risk

A recent study of BU, Fludarabine and 400 cGy of TBI showed a low TRM(3%) and a projected DFS of 65%

J Clin Oncol 2000; 18: 340–347.

ALL A comparative analysis of

TBI combined with either CY or etoposide chemotherapy showed no TRM differences

In CR1, no significant differences in relapse, leukemia-free survival or survival by conditioning regimen

In CR2, the risks of relapse, treatment failure and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses 413 Gy.

Biol Blood Marrow Transplant 2006; 12: 438–453.

AML Cy-TBI appears to be superior to Bu-

Cy in terms of survival and LFS, especially in patients with advanced disease

Both TRM and relapse are reduced in patients undergoing TBI

Early toxicity is an important problem with Bu, and higher incidences of VOD and hemorrhagic cystitis are reported

Experimental Hematology 31 (2003) 1182–1186

IBMTR

BUCY and CyTBI

Best Practice & Research Clinical HaematologyVol. 20, No. 2, pp. 295 e 310, 2007

Best Practice & Research Clinical HaematologyVol. 20, No. 2, pp. 295 e 310, 2007

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