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Cancers in HIV: A Growing Problem

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1 Cancers in HIV: A Growing Problem
Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)

2 AIDS Defining Cancers Kaposi’s sarcoma B-cell non-Hodgkin’s lymphoma
Primary CNS lymphoma Cervical cancer

3 Cancer Incidences in HIV in USA
Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005. Cancer Incidences in HIV in USA Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the United States during 1991–2005. A) US AIDS population by calendar year and age group. B) The estimated counts and standardized rates of AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. C) The estimated counts and standardized rates of non-AIDS-defining cancers among people living with AIDS in the United States by calendar year and age group. Of note, the bars for 0–12 year olds in panels (B) and (C) are difficult to see because of small numbers of cancers in this age group during 1991–2005 (122 AIDS-defining cancers and 25 non-AIDS-defining cancers). D) The estimated counts and standardized incidence rates of total cancers among people living with AIDS in the United States, stratified by AIDS-defining cancers, non-AIDS-defining cancers, and poorly specified cancers. Bars depict the estimated number of cancers, and points connected by lines depict incidence rates standardized to the 2000 US AIDS population by age group, race, and sex. Shiels M S et al. J Natl Cancer Inst 2011;103:

4 Categorizing Cancers in PWHA
AIDS Defining Cancer (decreasing) KS NHL (BL, CNS, DLCBL) Cervical Cancer ( added in 1993) Non AIDS defining Cancers (increasing) Anal Cancer Lung Cancer Hodgkin Lymphoma Liver Cancer Elevated risk but rare Merkel Carcinoma Leiomyosarcoma Salivary gland LEC Unchanged risk Breast Colorectal Prostate Follicular lymphoma 4

5 Cancer is the One of the Most Frequent Causes of Death in HIV-Infected Patients
Cause of Death 2000 2005 Cancer (all) 29% 34% Cancer - AIDS defining 16% 13% Cancer - Non-AIDS defining 21% Hepatitis (non cancer) 14% 12% Other infections 7% 4% Mortalité 2000 and 2005 studies: Bonnet et al., Cancer 101; 317:2004 and CID 48;633: 2009. 5

6 7 Notable Cancers in HIV Cancer
Relative Risk in U.S. people with AIDS vs. general pop (SIR ) Estimated cases/yr in US based on HIV/Cancer Match Registry data Etiologic agents Relationship with immune suppression (CD4 or AIDS) Kaposi sarcoma 22,100 735 KSHV +++ Non-Hodgkin lymphoma 53 1146 EBV Cervical cancer 4.2 85 HPV + Lung cancer 3.3 324 Tobacco Hodgkin lymphoma 13.6 174 ++ Anal cancer 20.7 226 Liver cancer 4.0 90 HCV, HBV, alcohol Refs: Engels AIDS 2006, Biggar JNCI 2007, Engels Int J Cancer 2008, Chaturvedi JNCI 2009, Guiguet Lancet Oncol 2009

7 Cancers in HIV Disease AIDS-Defining Virus Kaposi’s Sarcoma HHV-8
Non-Hodgkin’s Lymphoma EBV, HHV-8 (systemic and CNS) Invasive Cervical Carcinoma HPV Non-AIDS Defining Anal Cancer HPV Hodgkin’s Disease EBV Leiomyosarcoma (pediatric) EBV Squamous Carcinoma (oral) HPV Merkel cell Carcinoma MCV Hepatoma HBV, HCV

8 HIV-Cancers: Overview
Non-AIDS defining malignancies Anogenital neoplasia Lymphomas Kaposi’s Sarcoma Cancer Prevention

9 Non-AIDS Defining Cancers NADC

10 Non AIDS-defining Cancers Emerging Epidemiologic Features
Proportion of Cancers in HIV NADC 31% 58% Standardized Incidence Ratio Lung 2.6 Hodgkin lymphoma 2.8 6.7 Larynx 1.8 2.7 Pancreas 0.8 2.5 Liver 3.7 Engels EA, Int J Cancer. 2008;123:

11 Factors Contributing to the Increase in Cancer cases in HIV
4-fold increase in HIV/AIDS Population Patients living longer and not dying of OI Rising proportion of HIV pts > 50 yo Cancer incidence increases with age Greater and earlier start to smoking in HIV Increase in some CA incidence rate among HIV Lung (3X), anal (29X), liver (3X), HL (13X) Suggests may be additional risk from HIV

12 Pathogenesis of Cancer in HIV
Many are virally-induced cancers, but not all Immune activation, immune dysregulation, inflammation and decreased immune surveillance HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genes HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)1 Increase susceptibility to effects of carcinogens Endothelial/epithelial cell abnormalities induced or facilitated by HIV may allow for cancer development Population differences based on genetics and exposure to carcinogens Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26

13 Outcomes of cancer in HIV
With prolonged survival of HIV population and aging, more people will develop cancer, especially NADCs. HIV-infected cancer patients may have worse outcomes in some cancers Late presentation, advanced stage Poor access to care Medical comorbidity, treatment toxicity Unclear if HIV has adverse impact on cancer behavior, immune control, cancer-free survival Limited data for guiding cancer treatment in HIV-infected people Biggar JAIDS 2005, Little J Clin Oncol 2008, Rengan Lancet Oncol 2012, Suneja AIDS 2013

14 Anogenital Cancers

15 Anogenital Cancers Invasive cervical carcinoma Anal cancer1
Considered an AIDS-defining condition Leading cause of cancer death in women worldwide Anal cancer1 Not AIDS defining but very common and growing incidence Oral and Head/Neck cancer also HPV related HPV involvement1-2 Both derive from precancerous lesions due to HPV Most cancer causing strains: 16, 18, 31, 33, 35, 45 Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia Cancer can be prevented with early diagnosis and vaccines Slide #26: Cervical and Anal Cancers Invasive cervical cancer has been recognized as an AIDS-defining malignancy for nearly 10 years.1 Prevalence of abnormal cervical cytology as high as 60% in some centers. Nationwide, invasive cervical cancer was found in 1.3% of all women with AIDS and appears to be increasing. Martin and colleagues reported that the HIV-positive population was at increased risk of anal cancer.1,2 25 to 87 cases per 100,000 reported among homosexual men versus 0.7 cases per 100,000 across the overall male population. Cervical and anal cancers have similar etiologies:3 Progression of squamous intraepithelial lesions to invasive tumors. Other correlative features include comparable risk factors including receptive intercourse, smoking, and infection with high-risk and multiple genotypes of human papilloma virus (HPV). HPV involvement in both invasive cervical cancer and anal cancer within the HIV-positive population is correlated with certain oncogenic strains, including 16, 18, 31, 33, and These genotypes are associated with a high rate of proliferation of certain genes expressed during latent infection and may produce cellular immortalization within affected epithelial cells. References Mitsuyasu RT, Cooper JS. AIDS-related malignancies. In: Reckling S, ed. Cancer Management: A Multidisciplinary Approach. 5th ed. Melville, NY: PRR; 2001: Phelps RM, Smith DK, Heilig CM, et al. Cancer incidence in women with or at risk for HIV. Int J Cancer. 2001;94: Martin F, Bower M. Anal intraepithelial neoplasia in HIV-positive people. Sex Transm Infect. 2001;77: 1Phelps RM, et al. Int J Cancer. 2001;94: 2Martin F, et al. Sex Transm Infect. 2001;77:

16 Spectrum of HPV disease
Morphologic Continuum Low-grade disease High-grade disease

17 Dentate (pectinate) line External sphincter ani muscles
Anal anatomy Rectal mucosa Columns of Morgagni Dentate (pectinate) line Squamous mucosa Skin Levator ani muscle Subcutaneous Deep External sphincter ani muscles Superficial Ryan DP et al. New Engl J Med. 2000;342: 17

18 Anal and Cervical Cancer Incidence
Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000 Cervical cancer currently: 8-10/100,000 Anal cancer among HIV+ MSM in USA: up to 137/100,000 American Cancer Society. Cervical cancer facts Daling JR et al. N Engl J Med. 1987;317: Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.

19 Prevalence of anal HPV detection among MSM Population-based data
All participants HIV-negative participants HIV-seropositive participants Chin-Hong et al. Ann Int Med. 2008;149;300-6. 19 19

20 Redfield IRC 2100

21 Lymphomas

22 Pathology of AIDS-Related Non-Hodgkin’s Lymphoma
Small noncleaved-cell lymphoma Burkitt’s lymphoma and Burkitt-like lymphoma Immunoblastic lymphoma (primary CNS) Diffuse large-cell lymphoma (90% CD20+) Large noncleaved-cell lymphoma CD30+ anaplastic large B-cell lymphoma Plasmablastic lymphoma Advanced stage (>75% III or IV) Extranodal involvement Central nervous system, liver, bone marrow, gastrointestinal Slide #15: Pathology of AIDS-Related Non-Hodgkin’s Lymphoma Non-Hodgkin’s lymphoma is among the most commonly diagnosed cancers in the patients with HIV disease.1 Two main histologic categories:1 Small noncleaved-cell lymphoma (SNCCL). Include Burkitt’s lymphoma and Burkitt-like lymphoma Make up 40% of all cases of non-Hodgkin’s lymphoma. Diffuse large-cell lymphoma (DLCL). Large noncleaved-cell lymphoma and immunoblastic lymphoma plasmocytoid are the most prevalent types of DLCLs, and they represent 25% each of all non-Hodgkin’s lymphomas. CD30+ anaplastic large B-cell lymphoma is another AIDS-related non-Hodgkin’s lymphoma. It is important that these lymphomas are accurately diagnosed and categorized as either SNCCL or DLCL, as the lymphoma type reveals pertinent information regarding the prognosis.1 Reference 1. Tirelli U, Spina M, Gaidano G, Vaccher E, Franceschi S, Carbone A. Epidemiological, biological, and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy. AIDS. 2000;14: Tirelli U, et al. AIDS. 2000;14:

23 EBV-positive tumors Burkitt’s lymphoma Nasopharyngeal carcinoma 23

24 AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General Population Besson et al. Blood. 2001; 98: Little et al Blood. 2003; 101:

25 Hodgkin’s Disease Association with HIV-infection
Hodgkin’s disease: RR: 5 to 30 Non-Hodgkin’s disease: RR: 24 to 165 Incidence increasing rapidly in post HAART era >95% are EBV+ Patients with HIV present with: B symptoms (70% to 96%), worse histology, higher-stage tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia Good response to MOPP/ABV Complete response: 74.5% 2-year disease-free survival: 62% but more relapses in HIV Early good results with Stanford V, BEACOPP and brentuximab vendotin Slide #32: Hodgkin’s Disease Hodgkin’s disease is associated with HIV disease, however this association is lower than that seen with non-Hodgkin’s lymphoma (relative risk: 5-30 vs , respectively).1,2 HIV-infected patients diagnosed with Hodgkin’s disease frequently present with:1,2 B symptoms that are typically associated with poorer prognoses. These symptoms include fever, night sweats, and loss of more than 10% of body weight. Higher grade of disease than is found in newly diagnosed patients who are not HIV-positive. <1% of all patients with Hodgkin’s disease exhibit lymphocyte depletion. However, most of these cases are found in patients with HIV. Indicative if advanced disease, there is a greater chance of bone marrow involvement and pancytopenia being present at diagnosis. The MOPP/ABV regimen has produced good results, with a complete response rate of 74.5% and a 2-year disease-free survival rate of 62%.3 References Spina M, Vaccher E, Nasti G, Tirelli U. Human immunodeficiency virus-associated Hodgkin’s disease. Semin Oncol. 2000;27: Re A, Casari S, Cattaneo C, et al. Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer. 2001;92: Gerard L, Galicier L, Boulanger E, et al. Improved survival in HIV-related Hodgkin’s lymphoma since the introduction of highly active antiretroviral therapy. AIDS. 2003;17:81-87. Gerard L, et al. AIDS. 2003;17:81-87.

26 Kaposi’s Sarcoma

27 Kaposi’s Sarcoma One of the first recognized AIDS-defining illnesses
Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sites Human herpesvirus-8 (HHV8) or KSHV HHV8 DNA virus found in both HIV+ and HIV- KS. Tropism for B cells and endothelial cells, high titers in saliva Also associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIV Genome codes for viral homologs of human proteins involved in cell cycle regulation and signaling HIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growth Slide #8: Characteristics of Malignancies in AIDS Kaposi’s sarcoma was one of the first AIDS-defining conditions.1 Once a rare cancer of elderly men of Mediterranean origin, it became epidemic in the early years of AIDS. Virus associated with Kaposi’s sarcoma.1 Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpes virus-8 (HHV8). HHV8 is sexually transmitted although it is not found in high concentrations in semen.2 Recent research has detected viral replication in the oropharynx, suggesting an oral route of transmission. If true, then high-risk behaviors would be expanded to include “deep kissing” and oral/genital contact; and it would be expected that high rates of infection would be seen within the heterosexual community. Instead, the prevalence of HHV8 in heterosexuals is low, and MSMs are more likely to develop Kaposi’s sarcoma than their heterosexual counterparts, except in Africa where the incidence of Kaposi’s sarcoma is approximately equal in the two genders. The possibility of oral transmission of KSHV raises many unanswered questions. Levine and Tulpule observed that while HAART has been directed at reducing HIV-induced immunosuppression, it has also been associated with a drop in the incidence of Kaposi’s sarcoma. The study of Kaposi’s sarcoma thus could yield insight into pathogenesis-based therapeutic interventions.3 References Osmond DH, Buchbinder S, Cheng A, et al. Prevalence of Kaposi’s sarcoma-associated herpesvirus in homosexual men at the beginning of and during the HIV epidemic. JAMA. 2002;287: Webster-Cyriaque J, Kendrick K. Detection of Kaposi’s associated herpesvirus in the oral cavity of immunocompetent and immunosuppressed individuals. International Association for Dental Research 80th General Session Abstract 1747. Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer. 2001;37:

28 AIDS-associated Kaposi’s Sarcoma
Transmission Mostly MSM in US IVDU and Heterosexual as well Resource limited setting – Africa and S. America KS still most common cancer in HIV Prevalence 1300 cases/100,000 persons/yr 1992 170 cases/100,000 persons/yr 2006 Decline of 10% / year Cause of considerable morbidity and mortality in Africa and Latin America

29 Clinical Manifestations
Mucocutaneous, macular or nodular, dark color Lymphadenopathy Visceral Often asymptomatic Mouth, esophagus, stomach, bowel, liver, spleen Pulmonary KS Rapidly fatal Dyspnea without fever, hemoptysis Diffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusions Edema, can be extensive and symptomatic

30 Kaposi’s Sarcoma

31

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33 Oral Kaposi’s Sarcoma

34 KS in Africa – A “Different” Disease?

35 Pulmonary KS on CXR & CT Scan

36 Treatments for Kaposi’s Sarcoma
Local1 Systemic1,2 Radiation therapy Photodynamic (laser) therapy Cryotherapy Alitretinoin gel – 9-cis retinoic acid (topical) Antiretroviral therapy Liposomal anthracyclines Paclitaxel Bleomycin Vinca alkaloids Gemcitabine Alpha Interferon Slide #9: Treatment for Kaposi’s Sarcoma Kaposi’s sarcoma lesions may be treated locally with various therapies.1 Efficacy of local radiation is variable, but this treatment may result in complete remission for some patients. Photodynamic (laser) therapy, intralesional chemotherapy (vinblastine or vincristine),cryotherapy, alitretinoin topical gel. Recurrence following remission induced by local therapy is quite common. Systemic therapy is useful for the treatment of visceral lesions that do not respond to other therapies, but efficacy varies greatly among patients.1,2 Interferon-alfa has a 30% response rate. Flu-like symptoms, neutropenia, peripheral neuropathy, and central nervous system effects are dose-limiting toxicities for this treatment. Liposomal anthracyclines are recommended as first-line therapy for advanced Kaposi’s sarcoma. Paclitaxel is recommended as second-line therapy for those who have failed the anthracyclines. Other systemic therapies include bleomycin, vinca alkaloids (such as vinblastine, vincristine, and vinorelbine), cytokines, retinoids, and antivirals, such as cidofovir. Toxicity is common with systemic therapy and may range from hair loss to myelosuppression and neurotoxicity, depending on the specific therapy.1 References Levine AM, Tulpule A. Clinical aspects and management of AIDS-related Kaposi’s sarcoma. Eur J Cancer. 2001;37: Mitsuyasu RT, Cooper JS. AIDS-related malignancies. In: Reckling S, ed. Cancer Management: A Multidisciplinary Approach. 5th ed. Melville, NY: PRR; 2001: 1Levine AM, et al. Eur J Cancer. 2001;37: 2Mitsuyasu RT, et al. Cancer Management. 2008:

37 Cancer Prevention Smoking Cessation – Highest priority
Hepatitis and HPV vaccination Yearly cervical and anal Pap tests – Gyn and HRA Maintain high index of suspicion for cancer Yearly breast, prostate (incl. PSA) exam Advise sun screen and avoid overexposure Complete family history for malignancies If Hepatitis B or C positive, follow LFTs and perhaps AFP periodically (?)

38 Summary As patients live longer with HIV, morbidity and mortality from cancers are increasing The types of cancers in HIV may vary in different populations around the world Treatment of malignancies in HIV should be vigorous and appropriate to the situation Side effects of therapy should be treated/prevented Prevention strategies for virally-associated malignancies in HIV need to be investigated Through prospective clinical trials research can treatment and prevention strategies be effectively evaluated Slide #44: Summary As patients live longer with HIV disease, we need to be alert to the development of cancers. Simultaneous treatment of HIV infection and cancer can make meaningful differences in patients’ lives. Treatment of side effects, including anemia, can make meaningful differences in patients’ quality of life. Groups like the AIDS Malignancy Consortium are working to sponsor and coordinate trials that can explore the best methods for treating these diseases and enabling patients to tolerate these treatments. Research contributes not only to improved treatment regimens but to our general understanding of the mechanisms of oncogenesis, viral proliferation, immune-system functions, and cell-cycle biochemistry.

39 A poster from California used to raise awareness about smoking among the gay and lesbian communities

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41 Thank You For information on AMC clinical trials see: For information on NCI programs in HIV cancer see: To refer for AMC clinical trials in LA, call UCLA CARE Center ask for Maricela Gonzalez or page/ Dr. Mitsuyasu,


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