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Goals of This Talk: • Review potential benefits of protons • Clinical protocols using protons • Review- What have we learned to date? Goals of This Talk: Review potential benefits of protons Clinical protocols using protons Review- What have we learned to date? Reasons for BMT in Leukemia • • • • • Poor prognosis chromosomal abnormalities Prior myelodysplasia Secondary AML Prolonged Induction Relapsing/Refractory Disease Reasons for BMT in Leukemia Poor prognosis chromosomal abnormalities Prior myelodysplasia Secondary AML Prolonged Induction Relapsing/Refractory Disease E.D. Thomas - 1990 Nobel Prize in Medicine • Pioneered bone marrow transplant conditioning regimen • Established single fraction, low dose rate TBI regimen along with Cytoxan • Used dogs and Cobalt sources in 1950s and 1960s. E.D. Thomas - 1990 Nobel Prize in Medicine Pioneered bone marrow transplant conditioning regimen Established single fraction, low dose rate TBI regimen along with Cytoxan Used dogs and Cobalt sources in 1950s and 1960s Late Effects • • • • • • • • Cataracts Growth & development Fertility & sexual function Pneumonitis Veno-occlusive disease Renal damage Psychosocial development Secondary malignancies Late Effects • • • • Cataracts Growth & development Fertility & sexual function Pneumonitis Late Effects • • • • Veno-occlusive disease Renal damage Psychosocial development Secondary malignancies Late Effects • Cataracts • Growth & development • Fertility & sexual function • Pneumonitis Late Effects • Veno-occlusive disease • Renal damage • Psychosocial development • Secondary malignancies Cataracts Growth & Development Secondary malignancies Psychosocial development Late Effects Renal damage Fertility & Sexual Function Pneumonitis Venoocclusive disease Late Effects: • Posterior subcapsular cataract • Almost all patients w/ single fraction • 18% with fractionated • Surgery almost always well tolerated • Steroids increase risk Cataracts Late Effects: Growth & Development • Endocrine dysfunction • growth hormone esp.. poor in those receiving prior craniospinal XRT • subclinical hypothyroidism in ~70% • subnormal sex steroid concentrations • Growth plate damage • Seen in chemo only regimens also Late Effects: Fertility & Sexual Function • > 95 % of males w/ permanent azoospermia – no change w/ fractionation • Most female patients stop menstruating, but some can recover ( 20%) • Some pregnancies documented Late Effects: Pneumonitis – Clinical Symptoms • • • • dyspnea fever non-productive cough hypoxia – Within 90 days of transplant – High mortality Classical ground glass appearance Late Effects: Pneumonitis – Pathology • edema and fibrin exudation • endothelial hypertrophy • thickened alveolar septa Late Pneumonitis w/ pulmonary fibrosis Late Effects: • TBI – Total dose – Dose rate – Fractionation • Patient Factors – – – – – Age Increased wt Male gender CML GVHD • Disease Pneumonitis • Infectious – Malignancy – Remission status – Original Stage – CMV – Pneumocystis – Fungal • Other Chemo • Lung XRT – – – – Bleomycin Cytoxan Ara C Busulfan – Mean Lung Dose – V20 – Previous thoracic irradiation Late Effects: Venoocclusive disease – Clinical Symptoms • • • • • sudden weight gain jaundice hepatomegaly ascites high bilirubin – Incidence • 10 - 20 % of patients, ~50% mortality Pathology - obliteration of small vessels More frequent w/ Busulfan Late Effects: • • • • Renal Damage Increase Cr, BUN, Decrease GFR Anemia, HTN, peripheral edema, inc. LDH Increased risk • Ara C • GVHD • TBI dose • Cyclosporine Amphotericin B Busulfan Late Effects: Secondary malignancies • Influenced by genetics, chemotherapy ( alkylating agents) • Witherspoon et al (Seattle) reported RR=6.69 in 2246 patients • Many B-cell lymphomas, sarcomas • Patients with genetic immunodeficiency at higher risk (i.e.. Wiskott Aldrich)