3Cancer 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 USANumber 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:
4Categorizing Cancers in PWHA AIDS Defining Cancer(decreasing)KSNHL (BL, CNS, DLCBL)Cervical Cancer ( added in 1993)Non AIDS defining Cancers (increasing)Anal CancerLung CancerHodgkin LymphomaLiver CancerElevated risk but rareMerkel CarcinomaLeiomyosarcomaSalivary gland LECUnchanged riskBreastColorectalProstateFollicular lymphoma4
5Breakdown of causes of death: France 2005 AIDSCancerHepatitis CCVDSuicideNon-AIDS infectionAccidentHepatitis BLiver diseaseOD / drug abuseneurologicrenalpulmonarydigestiveiatrogenicmetabolicpsychiatricotherunknownN = 937 deathsThis shows the breakdown of cause of death from a study of deaths in 2005 in people with HIV in France.The proportion of deaths due to AIDS is only 36%, leaving the majority due to other causes.Looking at detail in the causes of death, the most common after AIDS are non-AIDS malignancy, hepatitis C, cardiovascular disease, suicide and non-AIDS infection.ANRS EN19 Mortalité 2005PercentLewden JAIDS 2008, 48:590-9
6Cancers in HIV Disease AIDS-Defining Virus Kaposi’s Sarcoma HHV-8 Non-Hodgkin’s Lymphoma EBV, HHV-8(systemic and CNS)Invasive Cervical Carcinoma HPVNon-AIDS DefiningAnal Cancer HPVHodgkin’s Disease EBVLeiomyosarcoma (pediatric) EBVSquamous Carcinoma (oral) HPVMerkel cell Carcinoma MCVHepatoma HBV, HCV
9Non AIDS-defining Cancers Emerging Epidemiologic Features Proportion of Cancers in HIVNADC31%58%Standardized Incidence RatioLung2.6Hodgkin lymphoma2.86.7Larynx1.82.7Pancreas0.82.5Liver3.7Engels EA, Int J Cancer. 2008;123:
10Factors Contributing to the Increase in Cancer cases in HIV 4-fold increase in HIV/AIDS PopulationPatients living longer and not dyeing of OIRising proportion of HIV pts > 50 yoCancer incidence increases with ageGreater and earlier start to smoking in HIVIncrease in some CA incidence rate among HIVLung (3X), anal (29X), liver (3X), HL (11X)Suggests may be additional risk from HIV
12Anogenital Cancers Invasive cervical carcinoma Anal cancer1 Considered an AIDS-defining conditionLeading cause of cancer death in women worldwideAnal cancer1Not AIDS defining but very common and growing incidenceOral and Head/Neck cancer also HPV relatedHPV involvement1-2Both derive from precancerous lesions due to HPVMost cancer causing strains: 16, 18, 31, 33, 35, 45Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasiaCancer can be prevented with early diagnosis and vaccinesSlide #26: Cervical and Anal CancersInvasive cervical cancer has been recognized as an AIDS-defining malignancy for nearly 10 years.1Prevalence 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.1,225 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:3Progression 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, andThese 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.ReferencesMitsuyasu 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:
13Spectrum of HPV disease Morphologic ContinuumLow-grade diseaseHigh-grade disease
14Dentate (pectinate) line External sphincter ani muscles Anal anatomyRectal mucosaColumns of MorgagniDentate (pectinate) lineSquamous mucosaSkinLevator ani muscleSubcutaneousDeepExternal sphincter ani musclesSuperficialRyan DP et al. New Engl J Med. 2000;342:14
15Anal and Cervical Cancer Incidence Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000Cervical cancer currently: 8-10/100,000Anal cancer among HIV+ MSM in USA: up to 137/100,000American 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.
16Prevalence of anal HPV detection among MSM Population-based data All participantsHIV-negative participantsHIV-seropositive participantsChin-Hong et al. Ann Int Med. 2008;149;300-6.1616
18Pathology of AIDS-Related Non-Hodgkin’s Lymphoma Small noncleaved-cell lymphomaBurkitt’s lymphoma and Burkitt-like lymphomaImmunoblastic lymphoma (primary CNS)Diffuse large-cell lymphoma (90% CD20+)Large noncleaved-cell lymphomaCD30+ anaplastic large B-cell lymphomaPlasmablastic lymphomaAdvanced stage (>75% III or IV)Extranodal involvementCentral nervous system, liver, bone marrow, gastrointestinalSlide #15: Pathology of AIDS-Related Non-Hodgkin’s LymphomaNon-Hodgkin’s lymphoma is among the most commonly diagnosed cancers in the patients with HIV disease.1Two main histologic categories:1Small noncleaved-cell lymphoma (SNCCL).Include Burkitt’s lymphoma and Burkitt-like lymphomaMake 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.1Reference1. 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:
20AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent to General PopulationBesson et al. Blood. 2001; 98:Little et al Blood. 2003; 101:
21Hodgkin’s Disease Association with HIV-infection Hodgkin’s disease: RR: 5 to 30Non-Hodgkin’s disease: RR: 24 to 165Incidence 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%), pancytopeniaGood response to MOPP/ABVComplete response: 74.5%2-year disease-free survival: 62% but more relapses in HIVEarly good results with Stanford V, BEACOPP and brentuximab vendotinSlide #32: Hodgkin’s DiseaseHodgkin’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).1,2HIV-infected patients diagnosed with Hodgkin’s disease frequently present with:1,2B 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%.3ReferencesSpina 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.
23Kaposi’s Sarcoma One of the first recognized AIDS-defining illnesses Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sitesHuman herpesvirus-8 (HHV8) or KSHVHHV8DNA virus found in both HIV+ and HIV- KS.Tropism for B cells and endothelial cells, high titers in salivaAlso associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIVGenome codes for viral homologs of human proteins involved in cell cycle regulation and signalingHIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell growthSlide #8: Characteristics of Malignancies in AIDSKaposi’s sarcoma was one of the first AIDS-defining conditions.1Once a rare cancer of elderly men of Mediterranean origin, it became epidemic in the early years of AIDS.Virus associated with Kaposi’s sarcoma.1Kaposi’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.2Recent 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.3ReferencesOsmond 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:
24AIDS-associated Kaposi’s Sarcoma TransmissionMostly MSM in USIVDU and Heterosexual as wellResource limited setting – Africa and S. AmericaKS still most common cancer in HIVPrevalence1300 cases/100,000 persons/yr 1992170 cases/100,000 persons/yr 2006Decline of 10% / yearCause of considerable morbidity and mortality in Africa and Latin America
25Clinical Manifestations Mucocutaneous, macular or nodular, dark colorLymphadenopathyVisceralOften asymptomaticMouth, esophagus, stomach, bowel, liver, spleenPulmonary KSRapidly fatalDyspnea without fever, hemoptysisDiffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusionsEdema, can be extensive and symptomatic
32Treatments for Kaposi’s Sarcoma Local1Systemic1,2Radiation therapyPhotodynamic (laser) therapyCryotherapyAlitretinoin gel – 9-cis retinoic acid (topical)Antiretroviral therapyLiposomal anthracyclinesPaclitaxelBleomycinVinca alkaloidsGemcitabineAlpha InterferonSlide #9: Treatment for Kaposi’s SarcomaKaposi’s sarcoma lesions may be treated locally with various therapies.1Efficacy 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.1,2Interferon-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.1ReferencesLevine 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:
33Cancer Prevention Smoking Cessation – Highest priority Hepatitis and HPV vaccinationYearly cervical and anal Pap tests – Gyn and HRAMaintain high index of suspicion for cancerYearly breast, prostate (incl. PSA) examAdvise sun screen and avoid overexposureComplete family history for malignanciesIf Hepatitis B or C positive, follow LFTs andperhaps AFP periodically (?)
34SummaryAs patients live longer with HIV, morbidity and mortality from cancers are increasingThe types of cancers in HIV may vary in different populations around the worldTreatment of malignancies in HIV should be vigorous and appropriate to the situationSide effects of therapy should be treated/preventedPrevention strategies for virally-associated malignancies in HIV need to be investigatedThrough prospective clinical trials research can treatment and prevention strategies be effectively evaluatedSlide #44: SummaryAs 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.