Download HIV and Cancer

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)
AIDS Defining Cancers
• Kaposi’s sarcoma
• B-cell non-Hodgkin’s lymphoma
• Primary CNS lymphoma
• Cervical cancer
Number of people living with AIDS, AIDS-defining cancers,
Cancer Incidences
in inUSA
non-AIDS-defining
cancers, andin
all HIV
cancers
the USA
during 1991–2005.
Shiels M S et al. J Natl Cancer Inst 2011;103:753-762
Categorizing Cancers in PWHA
• AIDS Defining Cancer
(decreasing)
• Non AIDS defining
Cancers (increasing)
– KS
– Anal Cancer
– NHL (BL, CNS, DLCBL)
– Lung Cancer
– Cervical Cancer ( added in
1993)
– Hodgkin Lymphoma
• Elevated risk but rare
– Merkel Carcinoma
– Leiomyosarcoma
– Salivary gland LEC
– Liver Cancer
• Unchanged risk
– Breast
– Colorectal
– Prostate
– Follicular lymphoma
Cancer is the One of the Most Frequent Causes of
Death in HIV-Infected Patients
Cause of Death
2000
2005
29%
34%
Cancer - AIDS defining
16%
13%
Cancer - Non-AIDS defining
13%
21%
14%
12%
7%
4%
Cancer (all)
Hepatitis (non cancer)
Other infections
Mortalité 2000 and 2005 studies:
Bonnet et al., Cancer 101; 317:2004 and
CID 48;633: 2009.
7 Notable Cancers in HIV
Relative Risk in
U.S. people
with AIDS vs.
general pop
(SIR 1990-1995)
Estimated cases/yr
in US based
on 2004-7
HIV/Cancer
Match
Registry data
Etiologic agents
Relationship with
immune
suppression
(CD4 or AIDS)
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
EBV
++
Anal cancer
20.7
226
HPV
++
Liver cancer
4.0
90
HCV, HBV, alcohol
+
Cancer
Kaposi sarcoma
Refs: Engels AIDS 2006, Biggar JNCI 2007, Engels Int J Cancer 2008,
Chaturvedi JNCI 2009, Guiguet Lancet Oncol 2009
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
HIV-Cancers: Overview
• Non-AIDS defining malignancies
• Anogenital neoplasia
• Lymphomas
• Kaposi’s Sarcoma
• Cancer Prevention
Non-AIDS Defining Cancers
NADC
Non AIDS-defining Cancers
Emerging Epidemiologic Features
1991-1995
1996-2002
Proportion of Cancers in HIV
NADC
31%
58%
Standardized Incidence Ratio
Lung
2.6
2.6
Hodgkin
lymphoma
2.8
6.7
Larynx
Pancreas
1.8
0.8
2.7
2.5
0
3.7
Liver
Engels EA, Int J Cancer. 2008;123:187-194
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
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
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
Anogenital Cancers
Anogenital Cancers
• Invasive cervical carcinoma
– 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
1Phelps
2Martin
RM, et al. Int J Cancer. 2001;94:753-757.
F, et al. Sex Transm Infect. 2001;77:327-331.
Spectrum of HPV disease
Low-grade disease
High-grade disease
Morphologic Continuum
Anal anatomy
Rectal
mucosa
Columns of
Morgagni
Levator ani
muscle
Dentate
(pectinate)
line
External
sphincter ani
muscles
Deep
Subcutaneous
Superficial
Ryan DP et al. New Engl J Med. 2000;342:792-800.
Skin
Squamous
mucosa
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. 2006.
Daling JR et al. N Engl J Med. 1987;317:973-977.
Chin-Hong PU, Palefsky JM. Dermatol Ther. 2005;18:67-76.
Prevalence of anal HPV detection among MSM
Population-based data
100
HPV
HPV-HR
88
Prevalence, %
80
72
66
57
60
46
40
34
20
0
All participants
HIV-negative
participants
HIV-seropositive
participants
Chin-Hong et al. Ann Int Med. 2008;149;300-6.
19
Redfield IRC 2100
Lymphomas
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
Tirelli U, et al. AIDS. 2000;14:1675-1688.
EBV-positive tumors
Burkitt’s lymphoma
Nasopharyngeal carcinoma
AIDS-related Lymphoma Experience Suggests
Cancer Treatment Outcome Can be Equivalent
to General Population
100
Percent Survival
NCI EPOCH CD4 > 99
NCI EPOCH
1997-1998: HAART Era
50
1991-1994: Pre-HAART
NCI DLBCL non-AIDS
0
0
6
12
18
24
36
48
Months
Besson et al. Blood. 2001; 98: 2339-2344
Little et al Blood. 2003; 101: 4653-4659
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
Gerard L, et al. AIDS. 2003;17:81-87.
Kaposi’s Sarcoma
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
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
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
Kaposi’s Sarcoma
Oral Kaposi’s Sarcoma
KS in Africa – A “Different” Disease?
Pulmonary KS on CXR & CT Scan
Treatments for Kaposi’s Sarcoma
Local1
Systemic1,2
• Radiation therapy
• Antiretroviral therapy
• Photodynamic (laser)
therapy
• Liposomal
anthracyclines
• Cryotherapy
• Paclitaxel
• Alitretinoin gel – 9-cis
retinoic acid (topical)
• Bleomycin
• Vinca alkaloids
• Gemcitabine
• Alpha Interferon
1Levine
AM, et al. Eur J Cancer. 2001;37:1288-1295.
RT, et al. Cancer Management. 2008:609-632.
2Mitsuyasu
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 (?)
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
Thank You
• For information on AMC clinical trials see:
http://www.aidscancer.org
• For information on NCI programs in HIV
cancer see:
http://www.cancer.gov/cancertopics/types/AIDS
• To refer for AMC clinical trials in LA, call
UCLA CARE Center 310-557-1891 ask for
Maricela Gonzalez or page/email Dr.
Mitsuyasu, [email protected]