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HIV RELATED MALIGNANCIES

HIV RELATED MALIGNANCIES. Dr KASESE GABORONE ONCOLOGY CENTRE. INTRODUCTION. Cancer and Aids are both pandemics Shared characteristics: Both have social and emotional impact that goes beyond the physical disruption they cause Both attract billions of research funds

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HIV RELATED MALIGNANCIES

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  1. HIV RELATED MALIGNANCIES Dr KASESE GABORONE ONCOLOGY CENTRE

  2. INTRODUCTION • Cancer and Aids are both pandemics • Shared characteristics: • Both have social and emotional impact that goes beyond the physical disruption they cause • Both attract billions of research funds • Both receive priority over heart and mental health topics in news coverage and funding

  3. PROBLEMS • Research is rapid but data collection world wide takes years to compile. Results in problems with topicality and redundancy(title prepared in 2001 might loose relevance in 2005) • Specific anticancer therapy for HIV related malignancies have not been addressed

  4. Major publications on HIV are concerned on research and epidemiology(where drug companies spend money) • Radiotherapy and chemotherapy have a major role to play but there are only 200 articles and book chapters on the subject

  5. CURRENT FACTS • HIV patients have increased incidence of certain tumours • Kaposis sarcoma • Non-hodgkin lymphoma • Cervical cancer • Scc conjuctiva • Ano rectal carcinoma • Leiomyosarcoma in children

  6. Now evident over the past decade that HIV related malignancies are caused by oncogenic viruses • HIV is not a direct oncogene virus, does not result in genetic modifications affecting cellular replication but facilitates the development of cancers by removing the immune system (causative)

  7. HIV patients have an increased risk of developing other malignancies • Other common tumours are not frequent in aids patients therefore they are immune independent • HAART has decreased aids related illnesses but has increased the number of people living with aids. Aids is not cured and this means a cumulative risk of developing malignancies

  8. Cancers developed do not necessarily contribute to the final cause of death of the patient because of competing risks of mortality from infection and other causes including treatment

  9. Principles of management of HIV related malignancies • Management of HIV related malignancies is set against a background of an underlying fatal disease • The usual oncological rules of practise do not apply • Very often the best decision is simply to treat with the simplest, most effective, palliative regimen available

  10. Individualised approach to decision making is more important • Protocol driven treatment is usually inappropriate • Patient should be fully involved in decisions concerning management of both HIV and of the malignant disease

  11. Management • Following options available • Active observation for asymptomatic disease • Local treatment (palliative or radical) for localised symptomatic disease • Systemic treatment(palliative or radical) for disseminated symptomatic disease

  12. Multidisciplinary clinic with the following disciplines represented • HIV/infectious diseases • Virology • Oncology (both radiation oncology and medical oncology and surgical oncologist) • HIV counselling • HIV nursing • Cancer nursing

  13. Same ethical rights to be given as any other patient • The right to be treated as a human being • The right to feel secure about the health program • The right to privacy • The right to service

  14. The right to understand the cost of treatment • The right to be advised of education or research activities • The right to counselling on refusal to receive treatment

  15. Specific management problems related to the coexistence of HIV and malignant disease • Impaired marrow function and impaired cellular immunity and therefore vulnerable to the myelosuppressive and immno-suppresive effects of anti-cancer therapy • Impaired nutritional status and physical status may limit the ability to withstand treatment

  16. Many of the arvs are themselves myelosuppressive and this further limits the delivery of orthodox cancer treatment • Important to identify concomitant treatments such as antibiotics, arvs, complementary therapies before starting cancer treatment

  17. Any HIV patient treated with drugs or radiation for malignant disease requires careful monitoring • Dose should be modified or treatment abandoned if excessive toxicity noted • Decisions to withdraw have to be rapid therefore good communication between oncologist, patient and primary care givers

  18. HIV itself may be more important than the tumour • Individualised approach to therapeutic decision making • Multidisciplinary clinic • Full involvement of patient in decision making

  19. Interactions with other treatments • Full drug history • Awareness of potential problems

  20. HIV related myelosuppression and immuno-suppression • Careful monitoring (clinical, FBC) • Prompt access to oncology services and supportive care • Prophylactic antiobiotics

  21. Fear and anxiety • Careful and sensitive communication • Psychological support

  22. Prognostic factors in HIV related malignancies • Extent and bulk of tumour • CD4 count (worse if less than 200) • Weight loss of more than 10% over 6 months • Night sweats

  23. History of opportunistic infection • Evidence of encephalopathy: dementia, confusion • Karnovsky status of less than 70% • NB. Features are not absolute contraindications to radical treatment but indicate poor tolerance

  24. Anti-retroviral therapy • Introduction has transformed the management of clinical consequences of HIV infection • Use of protease inhibitors associated with a decline in incidence of KS

  25. Essential principles of arvs are similar to those of chemotherapy • Use multiple drugs synchronously rather than sequentially • Use drugs with different modes of action • Use drugs with non-overlaping toxicities

  26. Specific tumours • Kaposis Sarcoma • First described by Moriz Kaposi in 1872 on five patients presenting with ‘sarcoma idiopaticum multiple hemorrhagicum’ • In 1912 Sternberg termed this disease Kaposi’s sarcoma-now refered as classsical KS • An indolent tumour seen typically in men of mediterranean or east European Jewish origin

  27. In 1914 Hallenberg described the first case of African or endemic KS • In 1960 the first report of KS following organ transplant and immuno-suppressive therapy • In 1981 Hymes described the epidemic form associated with AIDS

  28. Aetiology and pathogenesis • KS associated with gamma-2 herpes virus known as HHV-8(KSHV) • Virus identified using PCR-based techniques in all forms of KS • Classical • Endemic african • Paediatric • Epidemic(HIV related)

  29. HHV-8 transmitted in saliva • In homosexual men rate of HHV-8 is related to the number of sexual partners • Recent evidence from africa on HHV-8 prevelence in children suggests infection is acquired through normal social contacts within the family

  30. In developed countries seroprevalence of HHV-8 in general population is between 5 and 15%. For HIV positive homosexual men it is 30% • In africa prevalence is higher and increases with age: <2% under the age of 5; 15% for ages between 15 and 40 and >27% for older than 40

  31. Action of HHV-8 in development of KS • Production of an analogue of cyclin D which increase the propotion of cycling cells • Production of a bcl-2 analogue(vbcl-2) and a protein (vFLIP) both which will prevent apoptosis • Stimulation of angiogenesis mediated by a G protein coupled receptor (GPCR)

  32. Production of angiogenic proteines which are also inhibitory to macrophages (vMIPs)

  33. Epidemiology • Most frequent neoplasm in AIDS patients • First malignancy to be described in AIDS • Indirectly contributed to the identification of AIDS itself • Two previous rare disease found together then something unexpected is happening • Unexpected event was an epidemic

  34. The conditions were KS and PCP • The defined social group was homosexual male community • By 1998 nearly 57000 people in the USA had developed KS as a result of HIV • Swiss cohort study showed a significant decrease of KS in mid 90s due to HAART

  35. Clinical features • Classic lesion of KS is a raised macule purplish in calour • Lesions may coalesce into plaques and may ulcerate and bleed • KS may develop at sites of previous trauma • Oedema is almost always a feature • Visceral

  36. Examples of KS lesions

  37. Staging • Stage I <10 lesions or one anatomic area • Stage II >10 lesions or >anatomic site • Sage III Visceral only • Stage IV cutaneous and viscral

  38. Treatment • HAART • Local treatment • Cryotherapy • Photodynamic therapy • Intralesional injection • Radiation therapy

  39. Systemic therapy • Immunotherapy-interferon alfa • Chemotherapy • ABV • Liposomal doxorubicin • Taxol

  40. Experimental approaches • Antiangiogenasis approach • Thalidomide • Interleukin 2 • Anti-kaposis associated herpes virus • ganciclovir

  41. Non-hodgkin lymphoma Recognised as part of AIDS in 1982 Characteristically aggressive and often involve extra nodal sites

  42. Aetiology and pathogenesis • Some HIV individuals are more prone to develop lymphoma than others • Related to particular variants of the chemokine receptor gene, CCR5 • Potentiation of the carcinogenic effect of Epstein-Barr virus (EBV) and Human herpes virus-8 (HHV-8)

  43. Lymphomas develop against a background of chronic antigenic stimulation and most are of B-cell origin • Cytokenes stimulate expansion once malignant transformaton has occurred(IL-6, TNF-beta and IL-10) • Chemokines produced by HIV infected macrophages and monocytes produce autocrine stimulation of the abnormal clone

  44. Clinico-pathological categories of HIV related lymphomas • Diffuse large cell lymphoma(DLCL) • Large non cleaved (LNCCL) ebv 40% • Immunoblastic plasmacytoid (IBPL) 90% • Burkitt’s lymphoma (BL) ebv 30% • Primary lymphomas of the central nervous system(PCNSL) ebv 100% • Primary effusion lymphomas (PEL) ebv 90%, HHV-8 100%

  45. Degree and duration of HIV affects type of lymphoma that developes • Primary CNS lymphomas are associated with profound immunosuppression and occur late in the course of HIV • The other types may occur early

  46. Epidemiology Less than 5% aids defining diagnosis in developed countries but cause 15% of aids related deaths(occures late in the course) HAART has changed the pattern Extranodal lymphomas more common in AIDS patients

  47. Relative risk of AIDS compared to general population • Burkitts 261 • High grade difuse 652 • Intermediate grade 113 • Low grade 14

  48. Clinical features • Primary CNS • 75% develop in known AIDS patients • 50% have CD4 of less than 50/dl • Symptoms similar to SOL (headache, change in consciousness, focal neurological symptoms, visual disturbances) • Rapid onset and therefore difficult to differentiate from infection

  49. Nodal NHL including Burkitt’s • Wide spread nodal disease • Unusual nodal sites • Occipital • Epitrochlear • parotid • Involvement of bone marrow present in 25% • Direct involvement of overlying skin

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