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Non-Hodgkin's Lymphoma - Long-term Survivors and Adverse Effects

Non-Hodgkin's Lymphoma - Long-term Survivors and Adverse Effects. Ron Epelbaum. Department of Oncology Rambam Medical Center Haifa, Israel. Aggressive NHL 26-73% (5 y) Low-grade NHL 50-80% (10 y). Non-Hodgkin's Lymphoma - Long-term Survival. Late Effects of Therapy.

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Non-Hodgkin's Lymphoma - Long-term Survivors and Adverse Effects

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  1. Non-Hodgkin's Lymphoma - Long-term Survivors and Adverse Effects Ron Epelbaum Department of Oncology Rambam Medical Center Haifa, Israel

  2. Aggressive NHL 26-73% (5 y) Low-grade NHL 50-80% (10 y) Non-Hodgkin's Lymphoma - Long-term Survival

  3. Late Effects of Therapy • Toxicities that developed during therapy and continued after therapy • New toxicities that occurred after therapy was completed

  4. Late Toxicity Long-term Survival Diagnosis Treatment Acute Toxicity

  5. Long-Term Sequelae of Treatment for Non-Hodgkins Lymphoma Secondary malignancies Gonadal dysfunction Neurologic impairment Pulmonary toxicity Cardiac toxicity Others: Endocrine toxicity Immune system abnormalities Psychological problems Other organ toxicities

  6. Leukemia Lung Cancer non-Hodgkin's Lymphoma Bladder Cancer Gastric Cancer Secondary Malignancies

  7. All SM ANLL Solid SM Moertel, 1957 = = = Berg, 1967 = = = MacDoagall, 1981 = = = Storm, 1985 = = Greene, 1985 = Lavey, 1990 = = Lishner, 1991 = = Travis, 1993 Haddy, 1998 = = = Brennan, 2000 = Risk for Secondary Malignancies (SM) Secondary Malignancies

  8. HD NHL (20%) (21.1%) all second cancer all second cancer 0.4 0.3 0.2 0.1 0.0 25 20 15 10 5 0 Probability Cumulative Risk (%) 60 120 180 240 5 10 15 20 0 0 Time (months) Years from diagnosis of Non-Hodgkin's Lymphoma (n = 1939 patients with Hodgkin's disease) (n = 6171 two-year survivors of NHL) Van Leeuwen, JCO 1994 Travis, JNCI 1993 Cumulative Risk of Second Cancers Secondary Malignancies

  9. ANLL Solid Tumors HD (6292 pts) 70.80 2.40 NHL (6171 pts) 4.83 1.28 Obsereved to expected Ratio (O/E) Secondary Malignancies

  10. Total 2-4y 5-9y 10-14y >15y No. of NHL survivors 6171 6171 4496 2635 977 No. of ANLL 14 4 8 2 0 (%) (0.22) (0.06) (0.17) (0.07) 0 O/E for ANLL 4.83 5.00 6.90 3.08 - Travis et al., JNCI, 1993 ANLL Grouped by Time since Diagnosis of NHL Secondary Malignancies

  11. Total 2-4y 5-9y 10-14y >15y No. of NHL survivors 6171 6171 4496 2635 977 No. Solid tumors 586 133 194 110 49 (%) (7.8) (2.1) (4.3) (4.17) (5.0) O/E for Solid tumors 1.28 1.21 1.28 1.31 1.37 Travis et al., JNCI, 1993 Solid Tumors Grouped by Time since Diagnosis of NHL Secondary Malignancies

  12. O/E Latent period (y) Storm, 1985 3.8 Travis, 1994 4.8 7.5 Lavey, 1990 8.3 5.9 Pederson-Bjergaard, 1985 76.0 4.2 Gomez, 1982 341.0 3.8 Post-Therapeutic ANLL Secondary Malignancies

  13. Risk Factors for ANLL Drugs Alkylating agents Drugs binding to the enzyme Topoisomerase II Irradiation Large fields High doses Procedure ASCT Secondary Malignancies

  14. Drugs as Risk Factors for ANLL O/E Prednimustine13.4 related to cumulative dose and duration of treatment Mechlorethemin + Procarbozine12.6 Chlorambucil2.4 related to cumulative dose and duration of treatment Cyclophosphamide1.8 (NS) VP-16case reports Secondary Malignancies

  15. Radiation (RT) as Risk Factors for ANLL (O/E) RT RT RT RT alone dose field & CT Gomez, 1982 1 local RT = 1 TLI = 162 TLI+CT = 1008 Greene, 1983 RT+CT = 105 Lavey, 1990 1 TLI+CT = 10.6 CT alone = 11.9 Travis, 1994 3.1 (NS) 1 RT+CT = CT Travis, 1996 TBI+CT = 117 Secondary Malignancies

  16. Post-Transplant MDS/AML Crude incidence Actuarial (time-median) Risk (time) Sobesks, 1999 1.0% (1.5 y) Miligan, 1999 3.0% (5 y) Dark, 2000 2.8% (2.5 y) 6.3% (10 y) Darrington, 1994 4.0% (3.5 y) 12.0% (5 y) Stone, 1994 7.6% (2.5 y) 18.0% (6 y) Micallef, 2000 12.0% (6 y) 14.2% (5 y) 36.5% (10y) Miller, 1994 14.0% (5 y) Secondary Malignancies

  17. Risk Factors for Secondary MDS/AML Post Transplant • Old Age • Long interval between diagnosis and transplant • Low grade histology • Use of radiation therapy (TBI; Pelvic irradiation) • Bone marrow involvement at diagnosis • Prior fludarabine therapy • Low platelet count at the time of transplant Secondary Malignancies

  18. Etiology of Secondary MDS/AML Post-Transplant • Prior alkylator therapy • Transplant-related factors: • - Residual damaged host cells • - Altered bone marrow microenvironment which promote growth of mutated stem cell within the reinfused marrow Secondary Malignancies

  19. Post-Therapeutic Solid Tumors Lung Bladder Stomach Sarcoma Tongue/Lip Melanoma Libshitz, 1978 Konits, 1982 Green, 1985 Pedersen- Bjergaard, 1988 Lishner, 1991 Travis, 1993/95 Yamada, 1999 Brennan, 2000 Secondary Malignancies

  20. Risk Factors for Solid Tumors Drugs Cyclophosphamide (bladder, lung) Shared etiologic factors: Tobacco (lung) Sunlight exposure (melanoma, tongue/lip) Chemicals (sarcoma) Immunologic defects (melanoma) Genetic alterations Secondary Malignancies

  21. Secondary Malignancies Summary • Patients with NHL are at increased risk of second primary cancer. This risk, especially of solid tumors, remains high in long-term survivors. • The relative risk for ANLL has a wide range of 3.8-341, and for various solid tumors is up to 3.6. • The crude incidence of MDS/AML after transplant varies from 1% to 12%. The actuarial risk at 5 y is between 3% and 18%. • The excess risk of secondary malignancies is probably related to antecedent therapy and shared risk factors. Secondary Malignancies

  22. Gonadal Dysfunction

  23. Pre-Treatment - Males Lass, 1998 2/22 = 9.1%Azoospermia (HD = 18.2%) Pryzant, 1993 6/26 = 23%Oligospermia Naccache, 1996 13/24 = 54%Abnormal spermogram Botchan, 1997 HD>NHL>Controls Gonadal Dysfunction

  24. Post-Treatment Regimen Dysfunction Follow Up Time (median) Muller, 1993 MACOP-B 1/22 = 5% 2.3 y VACOP-B Radford, 1994 VAPEC-B 2/14 = 14% 1.1 y (NHL+HD) Bokemeyer, 1994 Various 4/24 = 17% all >2.0 y Dumontet, 1992 LNH-80 4/15 = 27% 9.2 y Pryzant, 1993 CHOP-Bleo 16/58 = 28% 2.7 y Gonadal Dysfunction

  25. Retention of Fertility after High-Dose Therapy and Transplant Fertility Test Jackson, 1997 10/23 = 43% Pregnancy (NHL+HD, <40y) Muller, 1993 5/10 = 50% Patient history, hormonal function Gonadal Dysfunction

  26. Preservation of Fertility Males Semen cryopreservation Females In-vitro fertilization and embryo storage Ovarian tissue cryopreservation Co-treatment with gonadotropin-releasing hormone agonist Gonadal Dysfunction

  27. Gonadal Dysfunction Summary • Patients with NHL have impaired pre-treatment sperm quality, compared with that of healthy controls. However, sperm quality is higher compared with HD. • Therapy of NHL induce long-term gonadal toxicity in up to 1/3 of the patients. Thus, fertility may be preserved in the majority of patients. • Fertility may be preserved also in patients receiving dose-intensification and transplant. • High cummulative doses of cyclophosphamide and pelvic irradiation are associated with a high risk of long-term sterility. Gonadal Dysfunction

  28. Neurotoxicity

  29. Professional activities Social activities Institutional care Death Primary CNS Lymphoma Encephalopathy after Treatment Clinical symptoms Dementia Ataxia Aphasia Hemiparesia Urinary incontinence CT / MRI Cortical thinning Ventricular enlargement White matter changes Neurotoxicity

  30. Treatment Probability Time to onset (median) O’Brien, 2000 MTX+RT 22% 13-30 m (+ IT-MXT) (16 m) Blay, 1998 CT (most HDMTX) 26% 5-105 m + RT (29 m) or RT alone Arbey, 1998 MTX+RT+ARA-C 32% 6-89 m (+ IT-MXT) Primary CNS Lymphoma Encephalopathy after CT+RT Neurotoxicity

  31. Primary CNS Lymphoma Encephalopathy - Risk Factors Age > 60 y CT after RT IT-MTX RT dose > 50 Gy CT dose Neurotoxicity

  32. Treatment Sandor, 1998 HDMTX + IT-MTX/ARA-C 14.0% Freiliech, 1996 MTX-based 7.7% Crossen, 1992 BBB disruption CT 0% Primary CNS Lymphoma Encephalopathy after CT alone Neurotoxicity

  33. Symptoms At the end At last of therapy follow-up Paresthesiae 78% 18% Muscle cramps 45% 13% Motor weakness 38% 8% Follow-up period: 3-34 months, median = 11 months Vincristine Peripheral Neuropathy (NHL + HD) Neurotoxicity Haim et al., CANCER 1994

  34. Central and/or Peripheral Neuropathy Drugs Procarbazine, Cytarabine, Fludarabine, Ifosfamide, Cisplatin Course Usually during treatment and reversible; may last for weeks to months, and rarely irreversible or progressive Neurotoxicity

  35. Neurotoxicity Summary • The probability of late central neurotoxicity in patients with primary brain lymphoma is 22-32% after chemotherapy combined with radiotherapy. • Less neurotoxicity is caused by chemotherapy alone for primary brain lymphoma. • The main risk factor for the development of late neurotoxicity is age >60y. • Various drugs used for lymphoma result in central or peripheral neurotoxicity. It is usually reversible, but may be associated with prolonged sequelae. Neurotoxicity

  36. Pulmonary Toxicity

  37. Pulmonary Toxicity Cause Irradiation, Chemotherapy Clinical Syndrome Pneumonitis, progressive fibrosis Signs & Symptoms Dyspnea, cough, fever Imaging Opacification, infiltrates, consolidation, nodules Lung Function Tests Decrease in lung volumes and in diffusing capacity Pulmonary Toxicity

  38. Bleomycin Dose Toxic findings No. Bechard, 1987 20 units fatal “bleomycin lung” 1 Quigley, 1988 <50 units/m2 pneumonitis 6/19 (31%) Low-dose Bleomycin Pulmonary Toxicity

  39. Regimen No. Patients % Toxicity Nagan, 1993 BACOP/m-BACOD 109 12.8 Rafi, 1997 CODBLAM IV 61 15.0 Boyd, 1988 COPBLAM III 51 39.0 Bleomycin-Containing Regimens Pulmonary Toxicity

  40. Regimen No. Patients % Toxicity Shapiro, 1991m-BACOD 134 18 m-ACOD 43 14 CHOP 30 0 Methotrexate-Containing Regimens Pulmonary Toxicity

  41. Regimen No. Patients % Toxicity Yokose, 1998 CHOP+G-CSF 52 11.5 Lei, 1994 BACOP+G-CSF 12 33.0 Chemotherapy with Granulocyte Colony-Stimulating Factor Pulmonary Toxicity

  42. After High-Dose Therapy and Transplant Pulmonary Toxicity No. Patients Respiratory complications Jules-Elysee, 1992 77 45% (NHL+HD) (26% fatal) Salloum, 1998 26 0% (NHL+HD)

  43. Cardiac Toxicity

  44. RT + Doxorubicin ... in Hodgkin's desease Cardiac Toxicity Coronary vessels Myocard Pericard Valves Conduction system

  45. Doxorubicin Related Short-term cardiac toxicity LVEF + symptoms Cardiac electrophysiology Late cardiac toxicity Time to cardiac Dose of Dox LVEF evaluation mg/m2 Haddy, 1998 0-13 y 80-240 1/28 = 4% median 9.9 y 240-560 7/29 = 24% Cardiac Toxicity

  46. I am a long-term survivor!!!

  47. Lung Injury Neurotoxicity Cardiac Damage Infertility Second Cancers

  48. Late effects

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