Ronald Mitsuyasu, MD Professor of Medicine Director, UCLA Center for Clinical AIDS Research and Education Group Chairman, AIDS Malignancy Consortium (AMC)

Ronald Mitsuyasu, MDRonald Mitsuyasu, MD

Professor of MedicineProfessor of Medicine

Director, UCLA Center for Clinical Director, UCLA Center for Clinical AIDS Research and EducationAIDS Research and Education

Group Chairman,Group Chairman,AIDS Malignancy Consortium (AMC)AIDS Malignancy Consortium (AMC)

Cancers in HIV:Cancers in HIV:A Growing ProblemA Growing Problem

AIDS Defining CancersAIDS Defining Cancers

• Kaposi’s sarcomaKaposi’s sarcoma

• B-cell non-Hodgkin’s lymphomaB-cell non-Hodgkin’s lymphoma

• Primary CNS lymphomaPrimary CNS lymphoma

• Cervical cancerCervical cancer

Number of people living with AIDS, AIDS-defining cancers, non-AIDS-defining cancers, and all cancers in the USA during 1991–2005.

Shiels M S et al. J Natl Cancer Inst 2011;103:753-762

Cancer Incidences in HIV in USA

Categorizing Cancers in PWHACategorizing Cancers in PWHA

• AIDS Defining CancerAIDS Defining Cancer

(decreasing)(decreasing)– KSKS

– NHL (BL, CNS, DLCBL)NHL (BL, CNS, DLCBL)

– Cervical Cancer ( added in Cervical Cancer ( added in 1993)1993)

• Non AIDS defining Non AIDS defining Cancers (increasing)Cancers (increasing)

– Anal CancerAnal Cancer

– Lung CancerLung Cancer

– Hodgkin LymphomaHodgkin Lymphoma

– Liver CancerLiver Cancer

• Elevated risk but rareElevated risk but rare

– Merkel CarcinomaMerkel Carcinoma

– LeiomyosarcomaLeiomyosarcoma

– Salivary gland LECSalivary gland LEC

• Unchanged riskUnchanged risk

– BreastBreast

– ColorectalColorectal

– ProstateProstate

– Follicular lymphomaFollicular lymphoma

Cancer is the One of the Most Frequent Causes of Cancer is the One of the Most Frequent Causes of Death in HIV-Infected PatientsDeath in HIV-Infected Patients

Cause of DeathCause of Death 20002000 20052005

Cancer (all)Cancer (all) 29%29% 34%34%

Cancer - AIDS definingCancer - AIDS defining 16%16% 13%13%

Cancer - Non-AIDS definingCancer - Non-AIDS defining 13%13% 21%21%

Hepatitis (non cancer)Hepatitis (non cancer) 14%14% 12%12%

Other infectionsOther infections 7%7% 4%4%

Mortalité 2000 and 2005 studies:Mortalité 2000 and 2005 studies:

Bonnet et al., Bonnet et al., CancerCancer 101; 317:2004 and 101; 317:2004 and

CIDCID 48;633: 2009 48;633: 2009..

7 Notable Cancers in HIV7 Notable Cancers in HIV

CancerCancer Relative Risk in Relative Risk in U.S. people U.S. people

with AIDS vs. with AIDS vs. general popgeneral pop

(SIR 1990-1995)(SIR 1990-1995)

Estimated cases/yr Estimated cases/yr in US based in US based on 2004-7 on 2004-7

HIV/Cancer HIV/Cancer Match Match

Registry dataRegistry data

Etiologic agentsEtiologic agents Relationship with Relationship with immune immune

suppression suppression (CD4 or AIDS)(CD4 or AIDS)

Kaposi sarcomaKaposi sarcoma 22,10022,100 735735 KSHVKSHV ++++++

Non-Hodgkin lymphomaNon-Hodgkin lymphoma 5353 11461146 EBVEBV ++++++

Cervical cancerCervical cancer 4.24.2 8585 HPVHPV ++

Lung cancerLung cancer 3.33.3 324324 TobaccoTobacco ++

Hodgkin lymphomaHodgkin lymphoma 13.613.6 174174 EBVEBV ++++

Anal cancerAnal cancer 20.720.7 226226 HPVHPV ++++

Liver cancerLiver cancer 4.04.0 9090 HCV, HBV, HCV, HBV, alcoholalcohol

++

Refs: Engels AIDS 2006, Biggar JNCI 2007, Engels Int J Cancer 2008, Chaturvedi JNCI 2009, Guiguet Lancet Oncol 2009

Cancers in HIV DiseaseCancers in HIV DiseaseAIDS-DefiningAIDS-Defining VirusVirus

• Kaposi’s SarcomaKaposi’s Sarcoma HHV-8HHV-8

• Non-Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma EBV, HHV-8EBV, HHV-8

(systemic and CNS)(systemic and CNS)

• Invasive Cervical CarcinomaInvasive Cervical Carcinoma HPVHPV

Non-AIDS DefiningNon-AIDS Defining

• Anal CancerAnal Cancer HPVHPV

• Hodgkin’s DiseaseHodgkin’s Disease EBVEBV

• Leiomyosarcoma (pediatric)Leiomyosarcoma (pediatric) EBVEBV

• Squamous CarcinomaSquamous Carcinoma (oral)(oral) HPV HPV

• Merkel cell CarcinomaMerkel cell Carcinoma MCVMCV

• HepatomaHepatoma HBV, HCVHBV, HCV

HIV-Cancers: OverviewHIV-Cancers: Overview

• Non-AIDS defining malignanciesNon-AIDS defining malignancies

• Anogenital neoplasiaAnogenital neoplasia

• LymphomasLymphomas

• Kaposi’s SarcomaKaposi’s Sarcoma

• Cancer PreventionCancer Prevention

Non-AIDS Defining CancersNon-AIDS Defining CancersNADCNADC

Non AIDS-defining CancersNon AIDS-defining CancersEmerging Epidemiologic FeaturesEmerging Epidemiologic Features

1991-19951991-1995 1996-20021996-2002

Proportion of Cancers in HIVProportion of Cancers in HIV

NADC NADC 31% 31% 58%58%

Standardized Incidence RatioStandardized Incidence Ratio

LungLung 2.62.6 2.62.6

Hodgkin Hodgkin lymphomalymphoma 2.82.8 6.76.7

LarynxLarynx 1.81.8 2.72.7

PancreasPancreas 0.80.8 2.52.5

LiverLiver 00 3.73.7

Engels EA, Int J Cancer. 2008;123:187-194

Factors Contributing to the IncreaseFactors Contributing to the Increasein Cancer cases in HIVin Cancer cases in HIV

• 4-fold increase in HIV/AIDS Population4-fold increase in HIV/AIDS Population

• Patients living longer and not dying of OIPatients living longer and not dying of OI

• Rising proportion of HIV pts > 50 yoRising proportion of HIV pts > 50 yo

• Cancer incidence increases with ageCancer incidence increases with age

• Greater and earlier start to smoking in HIVGreater and earlier start to smoking in HIV

• Increase in some CA incidence rate among HIVIncrease in some CA incidence rate among HIV

– Lung (3X), anal (29X), liver (3X), HL (13X)Lung (3X), anal (29X), liver (3X), HL (13X)

– Suggests may be additional risk from HIVSuggests may be additional risk from HIV

Pathogenesis of Cancer in HIVPathogenesis of Cancer in HIV• Many are virally-induced cancers, but not allMany are virally-induced cancers, but not all

• Immune activation, immune dysregulation, inflammation Immune activation, immune dysregulation, inflammation and decreased immune surveillanceand decreased immune surveillance

• HIV may activate cellular genes or proto-oncogenes or HIV may activate cellular genes or proto-oncogenes or inhibit tumor suppressor genesinhibit tumor suppressor genes

• HIV induces genetic instability (e.g 6 fold higher number of HIV induces genetic instability (e.g 6 fold higher number of MA in HIV lung CA over non-HIV)MA in HIV lung CA over non-HIV)11

• Increase susceptibility to effects of carcinogens Increase susceptibility to effects of carcinogens

• Endothelial/epithelial cell abnormalities induced or Endothelial/epithelial cell abnormalities induced or facilitated by HIV may allow for cancer developmentfacilitated by HIV may allow for cancer development

• Population differences based on genetics and exposure to Population differences based on genetics and exposure to carcinogens carcinogens

Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26Wistuba Il, Pathogenesis of NADC: a review. AIDS Pt Care 1999;13:415-26

Outcomes of cancer in HIVOutcomes of cancer in HIV

• With prolonged survival of HIV population and aging, more people With prolonged survival of HIV population and aging, more people will develop cancer, especially NADCs.will develop cancer, especially NADCs.

• HIV-infected cancer patients may have worse outcomes in some HIV-infected cancer patients may have worse outcomes in some cancerscancers

– Late presentation, advanced stageLate presentation, advanced stage

– Poor access to carePoor access to care

– Medical comorbidity, treatment toxicityMedical comorbidity, treatment toxicity

• Unclear if HIV has adverse impact on cancer behavior, immune Unclear if HIV has adverse impact on cancer behavior, immune control, cancer-free survivalcontrol, cancer-free survival

• Limited data for guiding cancer treatment in HIV-infected people Limited data for guiding cancer treatment in HIV-infected people

Biggar Biggar JAIDS JAIDS 2005, Little 2005, Little J Clin Oncol J Clin Oncol 2008, Rengan 2008, Rengan Lancet Oncol Lancet Oncol 2012, Suneja 2012, Suneja AIDS AIDS 20132013

Anogenital CancersAnogenital Cancers

Anogenital CancersAnogenital Cancers

• Invasive cervical carcinomaInvasive cervical carcinoma– Considered an AIDS-defining conditionConsidered an AIDS-defining condition

– Leading cause of cancer death in women worldwideLeading cause of cancer death in women worldwide

• Anal cancerAnal cancer11

– Not AIDS defining but very common and growing incidenceNot AIDS defining but very common and growing incidence

• Oral and Head/Neck cancer also HPV relatedOral and Head/Neck cancer also HPV related

• HPV involvementHPV involvement1-21-2

– Both derive from precancerous lesions due to HPVBoth derive from precancerous lesions due to HPV

– Most cancer causing strains: 16, 18, 31, 33, 35, 45Most cancer causing strains: 16, 18, 31, 33, 35, 45

– Repeated infections and infection with multiple HPV strains Repeated infections and infection with multiple HPV strains increase the risk of developing neoplasia increase the risk of developing neoplasia

– Cancer can be prevented with early diagnosis and vaccinesCancer can be prevented with early diagnosis and vaccines1Phelps RM, et al. Int J Cancer. 2001;94:753-757.2Martin F, et al. Sex Transm Infect. 2001;77:327-331.

Spectrum of HPV diseaseSpectrum of HPV disease

Morphologic Continuum

Low-grade disease High-grade disease

Rectalmucosa

Columns ofMorgagni

Dentate(pectinate)

line

Squamousmucosa

Skin

Levator animuscle

Subcutaneous

DeepExternalsphincter ani

muscles Superficial

Anal anatomyAnal anatomy

Ryan DP et al. New Engl J Med. 2000;342:792-800.

Anal and Cervical Cancer IncidenceAnal and Cervical Cancer IncidenceAnal and Cervical Cancer IncidenceAnal and Cervical Cancer Incidence

Cervical cancer prior to cervical cytology Cervical cancer prior to cervical cytology screening in general pop: 40-50/100,000screening in general pop: 40-50/100,000

Cervical cancer currently: 8-10/100,000Cervical cancer currently: 8-10/100,000 Anal cancer among HIV+ MSM in USA: Anal cancer among HIV+ MSM in USA:

up to 137/100,000up to 137/100,000

American Cancer Society. Cervical cancer facts. 2006.Daling JR et al. N Engl J Med. 1987;317:973-977.

Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.

19

Prevalence of anal HPV detection among MSMPrevalence of anal HPV detection among MSMPopulation-based dataPopulation-based data

Chin-Hong et al. Ann Int Med. 2008;149;300-6.

57

88

6672

34

46

0

20

40

60

80

100HPVHPV-HR

Pre

vale

nce

, %

HIV-seropositiveparticipants

HIV-negativeparticipants

All participants

Redfield IRC 2100Redfield IRC 2100

LymphomasLymphomas

Pathology of AIDS-RelatedPathology of AIDS-RelatedNon-Hodgkin’s LymphomaNon-Hodgkin’s Lymphoma

• Small noncleaved-cell lymphomaSmall noncleaved-cell lymphoma

– Burkitt’s lymphoma and Burkitt-like lymphoma Burkitt’s lymphoma and Burkitt-like lymphoma

• Immunoblastic lymphoma (primary CNS)Immunoblastic lymphoma (primary CNS)

• Diffuse large-cell lymphoma (90% CD20+)Diffuse large-cell lymphoma (90% CD20+)

– Large noncleaved-cell lymphomaLarge noncleaved-cell lymphoma

– CD30+ anaplastic large B-cell lymphomaCD30+ anaplastic large B-cell lymphoma

• Plasmablastic lymphoma Plasmablastic lymphoma

• Advanced stage (>75% III or IV)Advanced stage (>75% III or IV)

• Extranodal involvement Extranodal involvement

– Central nervous system, liver, bone marrow, gastrointestinalCentral nervous system, liver, bone marrow, gastrointestinalTirelli U, et al. AIDS. 2000;14:1675-1688.

EBV-positive tumors

Burkitt’s lymphoma Nasopharyngeal carcinoma

AIDS-related Lymphoma Experience Suggests AIDS-related Lymphoma Experience Suggests Cancer Treatment Outcome Can be Equivalent Cancer Treatment Outcome Can be Equivalent

to General Populationto General Population

0

50

100

0 6 12 18 24 36 48

Months

Pe

rce

nt

Su

rviv

al

NCI EPOCH CD4 > 99

NCI EPOCH

1997-1998: HAART Era

1991-1994: Pre-HAART

NCI DLBCL non-AIDS

Besson et al. Blood. 2001; 98: 2339-2344Little et al Blood. 2003; 101: 4653-4659

Hodgkin’s DiseaseHodgkin’s Disease

• Association with HIV-infectionAssociation with HIV-infection

– Hodgkin’s disease: RR: 5 to 30Hodgkin’s disease: RR: 5 to 30

– Non-Hodgkin’s disease: RR: 24 to 165Non-Hodgkin’s disease: RR: 24 to 165

– Incidence increasing rapidly in post HAART eraIncidence increasing rapidly in post HAART era

– >95% are EBV+>95% are EBV+

• Patients with HIV present with:Patients with HIV present with:

– B symptoms (70% to 96%), worse histology, higher-stage B symptoms (70% to 96%), worse histology, higher-stage tumor (74% to 92% are III or IV), bone marrow involvement tumor (74% to 92% are III or IV), bone marrow involvement (40% to 50%), pancytopenia(40% to 50%), pancytopenia

• Good response to MOPP/ABVGood response to MOPP/ABV

– Complete response: 74.5%Complete response: 74.5%

– 2-year disease-free survival: 62% but more relapses in HIV2-year disease-free survival: 62% but more relapses in HIV

– Early good results with Stanford V, BEACOPP and Early good results with Stanford V, BEACOPP and brentuximab vendotinbrentuximab vendotin

Gerard L, et al. AIDS. 2003;17:81-87.

Kaposi’s SarcomaKaposi’s Sarcoma

Kaposi’s SarcomaKaposi’s Sarcoma

• One of the first recognized AIDS-defining illnessesOne of the first recognized AIDS-defining illnesses

• Vascular tumor that may involve mucocutaneous, lymphatic, Vascular tumor that may involve mucocutaneous, lymphatic, gastrointestinal, and pulmonary sitesgastrointestinal, and pulmonary sites

– Human herpesvirus-8 (HHV8) or KSHVHuman herpesvirus-8 (HHV8) or KSHV

• HHV8 HHV8

– DNA virus found in both HIV+ and HIV- KS. DNA virus found in both HIV+ and HIV- KS.

– Tropism for B cells and endothelial cells, high titers in salivaTropism for B cells and endothelial cells, high titers in saliva

– Also associated with primary effusion lymphoma, Castleman’s Also associated with primary effusion lymphoma, Castleman’s disease, and angioimmunoblastic lymphadenopathy in HIV disease, and angioimmunoblastic lymphadenopathy in HIV

– Genome codes for viral homologs of human proteins involved in Genome codes for viral homologs of human proteins involved in cell cycle regulation and signalingcell cycle regulation and signaling

• HIV- and Kaposi’s sarcoma-induced angiogenic and HIV- and Kaposi’s sarcoma-induced angiogenic and inflammatory cytokines also stimulate Kaposi’s sarcoma cell inflammatory cytokines also stimulate Kaposi’s sarcoma cell growthgrowth

AIDS-associated Kaposi’s SarcomaAIDS-associated Kaposi’s Sarcoma

• TransmissionTransmission• Mostly MSM in USMostly MSM in US• IVDU and Heterosexual as wellIVDU and Heterosexual as well

• Resource limited setting – Africa and S. AmericaResource limited setting – Africa and S. America• KS still most common cancer in HIVKS still most common cancer in HIV

• PrevalencePrevalence• 1300 cases/100,000 persons/yr 1992 1300 cases/100,000 persons/yr 1992 • 170 cases/100,000 persons/yr 2006170 cases/100,000 persons/yr 2006• Decline of 10% / yearDecline of 10% / year• Cause of considerable morbidity and mortality in Cause of considerable morbidity and mortality in

Africa and Latin AmericaAfrica and Latin America

Clinical ManifestationsClinical Manifestations

• Mucocutaneous, macular or nodular, dark colorMucocutaneous, macular or nodular, dark color

• LymphadenopathyLymphadenopathy

• VisceralVisceral

• Often asymptomaticOften asymptomatic

• Mouth, esophagus, stomach, bowel, liver, spleenMouth, esophagus, stomach, bowel, liver, spleen

• Pulmonary KSPulmonary KS

• Rapidly fatalRapidly fatal

• Dyspnea without fever, hemoptysisDyspnea without fever, hemoptysis

• Diffuse reticulo-nodular infiltrates, mediastinal Diffuse reticulo-nodular infiltrates, mediastinal enlargement, pleural effusionsenlargement, pleural effusions

• Edema, can be extensive and symptomaticEdema, can be extensive and symptomatic

Kaposi’s SarcomaKaposi’s Sarcoma

Oral Kaposi’s SarcomaOral Kaposi’s Sarcoma

KS in Africa – A “Different” Disease?KS in Africa – A “Different” Disease?

Pulmonary KS on CXR & CT ScanPulmonary KS on CXR & CT Scan

Treatments for Kaposi’s SarcomaTreatments for Kaposi’s Sarcoma

• Radiation therapyRadiation therapy

• Photodynamic (laser) Photodynamic (laser) therapytherapy

• CryotherapyCryotherapy

• Alitretinoin gel – 9-cis Alitretinoin gel – 9-cis retinoic acid (topical)retinoic acid (topical)

• Antiretroviral therapy Antiretroviral therapy

• Liposomal Liposomal anthracyclinesanthracyclines

• PaclitaxelPaclitaxel

• BleomycinBleomycin

• Vinca alkaloidsVinca alkaloids

• GemcitabineGemcitabine

• Alpha InterferonAlpha Interferon

LocalLocal11 SystemicSystemic1,21,2

1Levine AM, et al. Eur J Cancer. 2001;37:1288-1295.2Mitsuyasu RT, et al. Cancer Management. 2008:609-632.

Cancer PreventionCancer Prevention

• Smoking Cessation – Highest prioritySmoking Cessation – Highest priority

• Hepatitis and HPV vaccinationHepatitis and HPV vaccination

• Yearly cervical and anal Pap tests – Gyn and HRAYearly cervical and anal Pap tests – Gyn and HRA

• Maintain high index of suspicion for cancerMaintain high index of suspicion for cancer

• Yearly breast, prostate (incl. PSA) examYearly breast, prostate (incl. PSA) exam

• Advise sun screen and avoid overexposureAdvise sun screen and avoid overexposure

• Complete family history for malignanciesComplete family history for malignancies

• If Hepatitis B or C positive, follow LFTs and If Hepatitis B or C positive, follow LFTs and

perhaps AFP periodically (?)perhaps AFP periodically (?)

SummarySummary

• As patients live longer with HIV, morbidity and As patients live longer with HIV, morbidity and mortality from cancers are increasingmortality from cancers are increasing

• The types of cancers in HIV may vary in different The types of cancers in HIV may vary in different populations around the worldpopulations around the world

• Treatment of malignancies in HIV should be vigorous Treatment of malignancies in HIV should be vigorous and appropriate to the situationand appropriate to the situation

• Side effects of therapy should be treated/preventedSide effects of therapy should be treated/prevented

• Prevention strategies for virally-associated Prevention strategies for virally-associated malignancies in HIV need to be investigatedmalignancies in HIV need to be investigated

• Through prospective clinical trials research can Through prospective clinical trials research can treatment and prevention strategies be effectively treatment and prevention strategies be effectively evaluatedevaluated

Thank YouThank You

• For information on AMC clinical trials see:For information on AMC clinical trials see:http://www.aidscancer.orghttp://www.aidscancer.org

• For information on NCI programs in HIV For information on NCI programs in HIV cancer see:cancer see:

http://www.cancer.gov/cancertopics/types/AIDShttp://www.cancer.gov/cancertopics/types/AIDS

• To refer for AMC clinical trials in LA, call To refer for AMC clinical trials in LA, call UCLA CARE Center UCLA CARE Center 310-557-1891 310-557-1891 ask for ask for Maricela Gonzalez or page/email Dr. Maricela Gonzalez or page/email Dr. Mitsuyasu, Mitsuyasu, [email protected]@mednet.ucla.edu