HIV Associated Malignancies. Dr.Prasad Abeysinghe Consultant Clinical Oncologist National Cancer Institute, Maharagama
Cancer has been linked to HIV since the earliest days of the epidemic. The unusually frequent occurrence of Kaposi sarcoma among men who have sex with men in 1981 was a sentinel observation leading to the inclusion of KS in the first AIDS case definition.
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Centers for Disease Control (CDC) classification. • AIDS-defining cancers (ADCs) KS, certain NHL subtypes, and cervical cancer • Non–AIDS-defining cancers (NADCs) all other cancers
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ADC/NADC distinction has major limitations as a cancer classification scheme • Cervical cancer and anal cancer • NHL and Hodgkin lymphoma
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The incidence of non–AIDS-defining cancers (NADCs) has increased by greater than 3-fold over the past 10 years and has now surpassed that of AIDS-defining cancers (ADCs) in HIV infected patients. • longer survival and aging of patients in the potent antiretroviral therapy era • Direct effects of HIV that increase susceptibility Prasad SLCV 18.10.2014
• Between 1989 and 2002 there has been an overall decline in cancer incidence from 77 cases to 12 cases per 1000 patient-years, reflecting a decline in incidence of ADC. • The incidence of NADCs increased from 3.3 to 10.9 cases per 1000 patient-years
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SLCVIntern 18.10.2014 Derived from data in Patel et Prasad al, Ann Med, 2008
There had been no obvious increase in breast, colon, or prostate cancers, although it is possible that increased risk will be observed for these malignancies with longer and closer follow-up.
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Increased life expectancy Co infection with viruses Behaviors and environmental toxins Direct effects of the virus and the consequences of long-term immuno suppression • Highly active antiretroviral therapy (HAART) therapy-may have effects on the host cell DNA, as well as on HIV, and could theoretically lead to genomic instability and carcinogenesis • • • •
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Co infection with viruses • Human herpes virus 8 (primary effusion lymphoma, Kaposi sarcoma, Castleman disease), • human papilloma virus (cervical, anal, penile, and possibly head and neck cancers), • Epstein-Barr virus (Hodgkin disease, NHL, primary central nervous system lymphoma,pediatric leiomyosarcoma) • HepatitisB and C viruses (hepatomas); Prasad SLCV 18.10.2014
Potential direct effects of HIV • HIV Tat protein transactivation of cellular genes or proto-oncogenes • Inhibition of tumor suppressor genes (eg,TP53) • Genetic instability • Increase the susceptibility of tissues to carcinogens • Elaboration of angiogenic factors, which could serve to facilitate tumor growth Prasad SLCV 18.10.2014
Highly active antiretroviral therapy (HAART)
• HAART consists of a combination of nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors(PI) • PIs are associated with apoptosis in vitro, and one may speculate that these may have a protective role against malignancy. • On the other hand, the other classes of antiretroviral therapy may have effects on the host cell DNA, as well as on HIV, and could theoretically lead to genomic instability and carcinogenesis. Prasad SLCV 18.10.2014
• Infection-related
• Infection unrelated
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For some cancers, only subsets of cases are caused by infection • NHL • Head and neck squamous cell carcinoma (HNSCC) Prasad SLCV 18.10.2014
Journal of Clinical Oncology, Vol 32, No 9 (March 20), 2014:
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different oncogenic viruses cause cancer by different mechanisms • Some viruses (eg, EBV for NHL)cause cancer by directly transforming infected cells. • In contrast, chronic hepatitis B and C infections are associated with increased risk of NHL through indirect mechanisms that likely involve chronic immune activation and B-cell stimulation. Prasad SLCV 18.10.2014
Molecular Insights to Guide Treatment • Treatment de-escalation is under active investigation in HPV-associated HNSCC, given the overall better prognosis for these tumors. • sorafenib (a type of targeted therapy known as a kinase inhibitor) may be a more effective treatment for hepatocellular carcinoma caused by hepatitisC than hepatitis B for reasons that have not been fully elucidated Prasad SLCV 18.10.2014
Issues in Management, Treatment, and Outcome HIV infected cancer patients have a worse prognosis • Likely to have more advanced disease. • ? Intensity of cancer therapy • Higher relapse rate( eg.Anal cancer and Hodgkin disease)
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Efficacy • Are standard treatments for each stage of each cancer in non–HIV-infected patients similarly effective in HIV-infected patients? • Does the presence of worse prognostic factors in HIV-infected patients require the use of more aggressive cancer therapy? • Are molecular and virally targeted therapies more or less appropriate for use in HIVinfected patients? Prasad SLCV 18.10.2014
Adverse Effects and Complications • Do HIV-infected patients experience additional and more severe toxicities from cancer therapies? • What are the pharmacokinetic and pharmaco dynamic drug interactions of HIV medications with cancer therapies? • How can HIV therapies and cancer therapies be adjusted to minimize toxicities? Prasad SLCV 18.10.2014
HIV-Specific Differences in Outcome of SCC of the Anal Canal
• In the era of HAART, HIV-positive patients with SCCAC are not optimally served with standard treatment regimens despite good tumor response rate and overall survival. They remain at increased risk for local relapse and enhanced acute toxicity. • In case of insufficient cancer control, HIV-positive individuals will likely succumb to cancer and not to HIV-associated diseases. Thus, CRT is challenged to be more efficient at reduced toxicity. Prasad SLCV 18.10.2014
Kaposi Sarcoma Treatment
• The sites of disease at presentation of epidemic KS are much more varied than the sites seen in other types KS. • In addition to antitumor treatment, essential components of an optimal KS treatment strategy include -highly active antiretroviral treatment (HAART), -prophylaxis for opportunistic infections, and -rapid recognition and treatment of intercurrent infections. Prasad SLCV 18.10.2014
• Local radiation therapy • Single agents or in combinations doxorubicin, bleomycin, vinblastine, vincristine, etoposide, paclitaxel, and docetaxel. • Pegylated liposomal doxorubicin • Interferon alphas • Bevacizumab, the humanized, antivascular, endothelial growth–factor monoclonal antibody Prasad SLCV 18.10.2014
Primary CNS Lymphoma • CT scans -ring enhancement in 50% of AIDS patients while patients without AIDS almost always show only homogeneous enhancement. • Both groups do equally poorly without therapy (1–3 month mean survival), but the overall survival for treated patients is much better for patients without AIDS (18.9 months) than for those with AIDS (2.6 months). Prasad SLCV 18.10.2014
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• • • •
No prior opportunistic infections or tumors for whom the CNS lymphoma is the AIDS-defining illness, and those patients with a good performance status, high CD4 lymphocyte count (>100mm3), and symptoms referable only to the CNS lymphoma. Radiation Therapy Combined Chemotherapy and Radiation Therapy Chemotherapy Alone-high-dose methotrexate alone (8 g/m2) Chemotherapy and Stem Cell Transplant Prasad SLCV 18.10.2014
AIDS-Related Lymphoma • Almost exclusively of B-cell tumors of aggressive type • All risk groups • CHOP • m-BACOD • Rituximab plus CHOP (R-CHOP) versus CHOP
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Optimized Cancer Screening and Prevention • cervical cancer screening intervals may need to be shorter in HIV-infected women • low-dose computed tomography (LDCT) for lung cancer screening. • screening for anal cancer-high resolution anoscopy • In patients who are hepatitis B virus or hepatitis C virus-seropositive, liver function tests and alpha-fetoprotein measurements Prasad SLCV 18.10.2014
• Smoking cessation may be the highest priority. • Hepatitis and HPV vaccination-differences in HPV subtypes, age at acquisition, and vaccine responsiveness • Sunscreen use and avoidance of overexposure to sunlight should be stressed
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In conclusion, • The ADC/ NADC distinction predates the modern ART era and has little scientific relevance. • Research efforts should be focused on individual cancers with underlying biologic mechanisms • Optimizing cancer screening and prevention strategies for HIV-infected populations is important Prasad SLCV 18.10.2014
• It is crucial that interactions among cancer chemotherapies, antiretroviral drugs, and other drugs routinely used in HIV-infected patients be identified
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